Penam derivatives and salts thereof, and antibacterial agent comprising the same

ABSTRACT

A penam derivative represented by the following general formula or a salt thereof: ##STR1## wherein R 1  represents a hydrogen atom, an amino-protecting group or an acyl group; R 2  represents a hydrogen atom or a lower alkyl group; R 3  represents a hydrogen atom, a lower alkoxy group, a lower alkylthio group or a formamido group; R 4  represents a protected or unprotected carboxy group or a craboxylato group; R represents a group of the formula, --NHR 5  or --NR 5  R 6  (in which R 5  and R 6 , which may be the same or different, represent protected or unprotected hydroxyl groups, cyano groups, sulfo groups, or unsubstituted or substituted lower alkyl, aryl, acyl, carbamoyl, sulfamoyl, lower alkylsulfonyl or heterocyclic groups) or a group of the formula, --N═CR 7  R 8  (in which R 7  and R 8 , which may be the same or different, represent hydrogen atoms or protected or unprotected carboxyl groups, cyano groups or unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, aryl, amino, acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, lower alkylthio, ureido or heterocyclic groups, or R 7  and R 8  may form a cycloalkene or a heterocyclic ring with the carbon atom to which R 7  and R 8  are attached); and n represents 1 or 2. The above penam derivative or its salt is very effective as antibacterial agents.

This invention relates to a novel penam derivative and a salt thereof,and more particularly, to a penam derivative represented by generalformula [I] as hereinafter described or a salt thereof, a process forproducing the same and an antibacterial agent containing the same.

Penam derivatives which are heretofore known, for example, compoundsdisclosed in Japanese Patent Application Kokai (Laid-Open) No.183588/1988 have a relatively broad antibacterial spectrum. However, theantibacterial activities of the compounds against resistant bacteria arenot satisfactory.

Under such circumstances, it has been desired that penam derivatives aredeveloped which have a broad antibacterial spectrum, are stable toβ-lactamases and exhibit a strong antibacterial activity againstresistant bacteria.

The inventors of this invention have made extensive research ondevelopment of a compound capable of solving the above-mentionedproblem, and consequently found penam derivatives of general formula [I]and salts thereof.

It is an object of this invention to provide a novel compound useful asa medicine for human beings and animals, which compound has a broadantibacterial spectrum, namely exhibits an excellent antibacterialactivity to Gram-positive bacteria and Gram-negative bacteria, and inparticular, is stable to β-lactamases and exhibits a strongantibacterial activity against resistant bacteria.

It is another object of this invention to provide a compound useful asan intermediate for the above-mentioned penam derivatives.

It is a further object of this invention to provide a processes forproducing the above-mentioned penam derivatives.

It is a still further object of this invention to provide anantibacterial agent comprising the above-mentioned penam derivatives.

Other objects and advantages of this invention will become apparent fromthe following description.

According to this invention, there is provided a penam derivativerepresented by general formula [I] or a salt thereof: ##STR2## whereinR¹ represents a hydrogen atom, an amino-protecting group or an acylgroup; R² represents a hydrogen atom or a lower alkyl group; R³represents a hydrogen atom, a lower alkoxy group, a lower alkylthiogroup or a formamido group; R⁴ represents a protected or unprotectedcarboxyl group or a carboxylato group; R represents a group of theformula, --NHR⁵ or --NR⁵ R⁶ (in which R⁵ and R⁶, which may be the sameor different, represent protected or unprotected hydroxyl groups, cyanogroups, sulfo groups or unsubstituted or substituted lower alkyl, aryl,acyl, carbamoyl, sulfamoyl, lower alkylsulfonyl or heterocyclic groups),or a group of the formula, --N═CR⁷ R⁸ (in which R⁷ and R⁸, which may bethe same or different, represent hydrogen atoms or protected orunprotected carboxyl groups, cyano groups or substituted orunsubstituted lower alkyl, lower alkenyl, lower alkynyl, aryl, amino,acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, lower alkylthio,ureido or heterocyclic groups, or R⁷ and R⁸ may form a cycloalkene or aheterocyclic ring with the carbon atom to which R⁷ and R⁸ are attached);and n represents 1 or 2.

In the present specification, the following terms have the followingdefinitions unless otherwise specified.

The term "halogen atom" means fluorine atom, chlorine atom, bromine atomand iodine atom; the term "lower alkyl group" means straight or branchedchain C₁₋₅ alkyl group such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl; the term "loweralkenyl group" means straight or branched chain C₂₋₅ alkenyl group suchas vinyl, allyl, isopropenyl, butenyl or 2-pentenyl; the term "loweralkynyl group" means C₂₋₅ alkynyl group such as ethynyl or 2-propynyl;the term "cycloalkyl group" means C₃₋₇ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the term "loweralkoxy group" means C₁₋₅ alkoxy group such as methoxy, ethoxy orpropoxy; the term "lower alkylthio group" means C₁₋₅ alkylthio groupsuch as methylthio, ethylthio or propylthio; the term "loweralkylthio-lower alkyl group" means C₁₋₅ alkylthio-C₁₋₅ alkyl group suchas methylthiomethyl, ethylthiomethyl or ethylthioethyl; the term"halo-lower alkyl group" means halogen-substituted C₁₋₅ alkyl group suchas chloromethyl, bromomethyl or trifluoromethyl; the term "hydroxy-loweralkyl group" means hydroxy-C₁₋₅ alkyl group such as hydroxymethyl,2-hydroxyethyl or 3-hydroxypropyl; the term "amino-lower alkyl group"means amino-C₁₋₅ alkyl group such as aminomethyl, 2-aminoethyl or3-aminopropyl; the term "carboxy-lower alkyl group" means carboxy-C₁₋₅alkyl group such as carboxymethyl, 2-carboxyethyl or 3-carboxypropyl;the term "lower alkoxycarbonyl-lower alkyl group" means C₁₋₅alkyl-O--CO--C₁₋₅ alkyl group such as methoxycarbonylmethyl,ethoxycarbonylmethyl or 2-ethoxycarbonylethyl; the term "cyano-loweralkylamino-lower alkyl group" means NC--C₁₋₅ alkyl-NH--C₁₋₅ alkyl groupsuch as cyanomethylaminomethyl or 2-cyanoethylaminomethyl; the term"N,N-di-lower alkylamino group" means N,N-di-C₁₋₅ alkylamino group suchas N,N-dimethylamino; the term "lower alkylsulfonyl group" means C₁₋₅alkylsulfonyl group such as methylsulfonyl or ethylsulfonyl; the term"sulfamoyl-lower alkyl group" means sulfamoyl-C₁₋₅ alkyl group such assulfamoylmethyl or 2-sulfamoylethyl; the term "lower alkoxycarbonylaminogroup" means C₁₋₅ alkyl-O--CO--NH-group; the term "lower alkoxyiminogroup" means C₁₋₅ alkyl-O--N═group; the term "cycloalkyloxyimino group"means C₃₋₇ cycloalkyl-O--N═ group; the term "lower alkylidene group"means C₁₋₅ alkylidene group such as methylidene or ethylidene; the term"lower alkenylidene group" means C₂₋₅ alkenylidene group such asethenylidene or propenylidene; the term "lower alkoxymethylene group"means C₁₋₅ alkyl-O--CH═ group; the term "halomethylene group" meanshalogen-substituted methylene group such as chloromethylene orbromomethylene; the term "lower alkanoyloxy group" means C₁₋₅alkyl-CO--O-- group; the term "lower alkoxycarbonyl group" means C₁₋₅alkyl-O--CO-- group; the term "carboxy-lower alkoxy group" meansHOOC--C₁₋₅ alkoxy group; the term "carboxy-lower alkylthio group" meansHOOC-- C₁₋₅ alkylthio group; the term "acyl group" means formyl group,C₂₋₅ alkanoyl group such as acetyl or propionyl C₃₋₅ alkenoyl group suchas acryloyl or crotonoyl, aroyl group such as benzoyl or naphthoyl orheterocyclic carbonyl group such as thenoyl, furoyl, isonicotinoyl,nicotinoyl, 1,4-dihydropyridin-2-ylcarbonyl or4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl; the term "acyloxy group" meansacyl-O-- group; the term "acylamino group" means acyl-NH-- group; theterm "aralkyl group" means benzyl group, phenethyl group, 4-methylbenzylgroup or naphthylmethyl group; the term "aryl group" means phenyl group,naphthyl group or indanyl group; the term "haloaryl group" meanshalogen-substituted aryl group; the term "N,N'-di-lower alkylaminoarylgroup" means N,N-di-C₁₋₅ alkylaminoaryl group such asN,N-dimethylaminophenyl; the term "arylamino group" means aryl-NH--group; the term "arylcarbonylamino group" means aryl-CO--NH-group; theterm "sulfamoylarylamino group" means H₂ NSO₂ -aryl-NH-- group; the term"aralkyloxyimino group" means aralkyl-O--N═ group; the term"cycloalkene" means C₅₋₆ cycloalkene such as cyclopentene orcycloheptene; the term "heterocyclic group" means 4- to 7-membered orcondensed or bridged heterocyclic group having 1-5 hetero atoms selectedfrom oxygen, nitrogen and sulfur atoms such as azetidinyl, thienyl,furyl, pyrrolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, thiazolyl,tetrazolyl, 1,3-dithiolanyl, pyridyl,1-hydroxy-4-oxo-1,4-dihydropyridyl, 1,4-dihydropyridyl, thiazolidinyl,oxazolidinyl, imidazolidinyl, pyrazolinyl, pyrrolidinyl, 2-oxazolinyl,imidazolinyl, furazanyl, isothiazolyl, 4,5-dihydrothiazolyl,2,3-dihydrofuryl, 2,5-dihydrofuryl, tetrahydrofuryl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl,pyrazolyl, 3-pyrrolinyl, 4,5-dihydropyrazolyl, isoxazolyl,isoxazolidinyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl,piperidinyl, piperazinyl, tetrahydropyrazinyl, morpholinyl, pyrimidinyl,pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-3,4-dihydropyranyl,2H-5,6-dihydropyranyl, 1,4-oxazinyl, pyridazinyl, 2H-thiazinyl,perhydrooxazinyl, dihydrooxazinyl, chromenyl, benzothienyl,benzoisothiazolidinyl, imidazo[1,2-b][1,2,4]triazinyl,thieno[3,2-b]thienyl, benzotriazolyl, 1,2,3-benzothiadiazolyl,tetrazolo[5,1-b]pyridazinyl, 2,1,3-benzoxadianyl, imidazo[1,2-a]pyridyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,2-b][1,3]thiazolyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrazinyl,1,4-benzomorpholinyl, benzothiazolyl, isoindolinyl, benzofuranyl,1,4-benzothiomorpholinyl, 1,3-benzoxazolidinyl,triazolo[1,5-a]pyrimidinyl, indolinyl, indazolyl, benzoxazolyl,benzoisoxazolyl, purinyl, isoquinolyl, quinolyl, 1,8-naphthyridinyl,1,5-naphthyridinyl, 1,1-dioxo-1,2-benzoisothiazolidinyl,1,2-dihydro-4H-3,1-benzoxazinyl, 1,2-benzoxazinyl, quinoxalinyl,quinazolinyl, cinnolinyl, indolyl, quinuclidinyl, perhydroazaepinyl or3-pyrrolin-2-yl; the term "heterocyclic amino group" means heterocyclicring-NH-- group; the term "heterocyclic oxyimino group" meansheterocyclic ring-O--N═ group; the term "heterocyclic thio group" meansheterocyclic ring-S-- group; and the term "heterocyclic ring" meansheterocyclic-H group. Incidentally, the heterocyclic group containing anitrogen atom as the hetero atom may be quaternized.

The amino-protecting group in the definition of R¹ includes usuallyknown amino-protecting groups, such as formyl, tert-butyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-amyloxycarbonyl, triphenylmethyl,trimethylsilyl, benzylidene, 2,2,2-trichloroethyloxycarbonyl orp-nitrobenzylidene and the like.

The acyl group in the definition of R¹ includes acyl groups which haveheretofore been known in the penicillin and cephalosporin fields, forexample, formyl, 2,6-dimethyloxyphenylcarbonyl,5-methyl-3-phenylisoxazol-4-ylcarbonyl and the like and acyl groupsrepresented by the formula: ##STR3## wherein R⁹ represents anunsubstituted or substituted lower alkyl, lower alkenyl, aryl orheterocyclic group; Z represents an oxygen or sulfur atom or a linkage;Y¹ represents a hydrogen atom; Y² represents a hydrogen atom, a halogenatom, a protected or unprotected hydroxyl group, a protected orunprotected carboxyl group, a sulfo group, a sulfoamino group, aprotected or unprotected amino group or a group of the formula, R¹⁰CONH-- in which R¹⁰ is an unsubstituted or substituted aryl,arylcarbonylamino, heterocyclic amino or heterocyclic group; and Y¹ andY² may form, when taken together, an unsubstituted or substituted loweralkoxyimino, cycloalkyloxyimino, aralkyloxyimino, lower alkylidene,lower alkenylidene, lower alkoxymethylene, halomethylene or heterocyclicoxyimino group.

In the definition of R⁹, the substituent for the substituted loweralkyl, lower alkenyl, aryl or heterocyclic group includes halogen atoms,hydroxyl group, amino group, amino-lower alkyl groups, acyloxy groups,carboxyl group, lower alkoxy groups, ureido group, acylamino groups,cyano group, sulfo group, carbamoyloxy group, sulfamoyl group, nitrogroup, oxo group, heterocyclic groups and the like. At least one of themmay be attached to the lower alkyl, lower alkenyl, aryl or heterocyclicgroup for R⁹ group.

In the definition of R¹⁰, the substituent for the substituted aryl,arylcarbonylamino, heterocyclic amino or heterocyclic group includes,for example, halogen atoms, hydroxyl group, oxo group, lower alkylgroups, halo-lower alkyl groups, hydroxy-lower alkyl groups, loweralkylthio groups, lower alkylthio-lower alkyl groups, aryl groups,haloaryl groups, cycloalkyl groups, arylamino groups, loweralkylsulfonyl groups and sulfamoylarylamino groups. At least one of themmay be attached to the aryl, arylcarbonylamino, heterocyclic amino orheterocyclic group for R¹⁰ group.

The substituent for the substituted lower alkoxyimino,cycloalkyloxyimino, aralkyloxyimino, lower alkylidene, loweralkenylidene, lower alkoxymethylene, halomethylene or heterocyclicoxyimino group which Y¹ and Y² may form when taken together includes,for example, halogen atoms, acyloxy groups and protected or unprotectedcarboxyl groups. At least one of them may be attached to the group whichY¹ and Y² may form.

In the definition of R¹, the acyl group represented by the formula,##STR4## wherein R⁹, Y¹, Y² and Z are as defined above includes,specifically 4-aminomethylphenylacetyl, hydroxyacetyl, phenoxyacetyl,1-tetrazolylacetyl, cyanomethylthioacetyl, carboxyethylthioacetyl,(2-thienyl)acetyl, α-bromo-α-(2-thienyl)acetyl,α-amino-α-(2-thienyl)acetyl, (5-methoxy-2-thienyl)acetyl, phenylacetyl,(3-bromophenyl)acetyl, α-aminophenylacetyl,α-amino-α-(p-hydroxyphenyl)acetyl,α-amino-α-(2-aminothiazol-4-yl)acetyl,α-sulfoamino-α-(4-acetyloxyphenyl)acetyl, α-hydroxyphenylacetyl,α-carboxyphenylacetyl, α-carboxy-α-(p-hydroxyphenyl)acetyl,α-carboxy-α-(o-hydroxyphenyl)acetyl,α-carboxy-α-(m-hydroxyphenyl)acetyl, α-carboxy-α-(p-fluorophenyl)acetyl,α-carboxy-α-(p-acetyloxyphenyl)acetyl,α-carboxy-α-(p-carbamoyloxyphenyl)acetyl,α-carboxy-α-(3-fluoro-4-hydroxyphenyl)acetyl,α-carboxy-α-(3,4-dihydroxyphenyl)acetyl,α-carboxy-α-(o-chlorophenyl)acetyl,α-carboxy-α-(3-chloro-4-hydroxyphenyl)acetyl,α-carboxy-α-(2-chloro-4,5-dihydroxyphenyl)acetyl,α-carboxy-α-(3,4-diacetyloxy-6-chlorophenyl)acetyl,α-carboxy-α-(2-thienyl)acetyl, α-carboxy-α-(3-thienyl)acetyl,α-sulfophenylacetyl, α-sulfo-α-(p-acetyloxyphenyl)acetyl,α-sulfo-α-(m-acetyloxyphenyl)acetyl, α-sulfo-α-(p-nitrophenyl)acetyl,α-sulfo-α-(p-aminophenyl)acetyl,α-sulfo-α-(2-chloro-5-nitrophenyl)acetyl,α-sulfo-α-(3,4-dihydroxyphenyl)acetyl,α-sulfo-α-(3,4-diacetyloxyphenyl)acetyl,α-sulfo-α-(4-acetyloxy-3-fluorophenyl)acetyl,α-sulfo-α-(3,4-diacetyloxy-5-chlorophenyl)acetyl,α-sulfo-α-(3,4-diacetyloxy-6-chlorophenyl)acetyl,α-sulfo-α-(3,4-diacetyloxy-2-chlorophenyl)acetyl,α-sulfo-α-(5-amino-2-chlorophenyl)acetyl,α-sulfo-α-(4-acetyloxy-3-chloro-6-fluorophenyl)acetyl,α-sulfo-α-(4-acetyloxy-6-fluorophenyl)acetyl,α-sulfo-α-(3,4-diacetyloxy-6-fluorophenyl)acetyl,α-sulfo-α-(o-chlorophenyl)acetyl, α-sulfo-α-(p-chlorophenyl)acetyl,α-sulfo-α-(2-aminothiazol-4-yl)acetyl,α-sulfo-α-(3,4-diacetyloxy-5,6-dichlorophenyl)acetyl,α-sulfo-α-(p-hydroxyphenyl)acetyl,α-sulfo-α-(2-chloro-4,5-dihydroxyphenyl)acetyl,α-sulfo-α-(4-acetyloxy-2-chlorophenyl)acetyl,α-sulfo-α-(4-acetyloxy-3-chlorophenyl)acetyl,α-sulfo-α-(3,4-diacetyloxy-5-fluorophenyl)acetyl,α-sulfo-α-(4-acetyloxy-3-nitrophenyl)acetyl,α-sulfo-α-(4-acetyloxy-2,5-dichlorophenyl)acetyl,α-sulfo-α-(4-acetyloxy-2-chloro-5-methoxyphenyl)acetyl,α-sulfo-α-(2-chloro-4-nitrophenyl)acetyl,α-sulfo-α-(4-amino-2-chlorophenyl)acetyl,α-sulfo-α-(4-ureidophenyl)acetyl,α-sulfo-α-(3-acetylamino-4-hydroxyphenyl)acetyl,α-sulfo-α-(2-chloro-4-hydroxyphenyl)acetyl,α-sulfo-αα-(2-fluoro-4-hydroxyphenyl)acetyl,α-sulfo-α-(3-fluoro-4-hydroxyphenyl)acetyl,α-sulfo-α-(2-chloro-4ureidophenyl)acetyl,α-sulfonylamino-α-(4-acetyloxyphenyl)acetyl,α-sulfo-α-(4,5-diacetyloxy-3-fluorophenyl)acetyl,α-sulfo-α-(3-fluoro-4,5-dihydroxyphenyl)acetyl,α-sulfo-α-(2-chloro-4-hydroxy-5-methoxyphenyl)acetyl,α-sulfo-α-(4-acetylaminocarbonyloxy-3-fluorophenyl)acetyl,α-formyloxy-α-phenylacetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(p-hydroxyphenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(p-acetyloxyphenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(methylthio)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(3,4-dihydroxyphenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(3,4-diacetyloxyphenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(3,4-diacetyloxy-6-chlorophenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(3,4-diacetyloxy-6-fluorophenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(6-chloro-3,4-dihydroxyphenyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(6-fluoro-3,4-dihydroxyphenyl)acetyl,α-(4-cyclopropyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(2-thienyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(3-benzothienyl)acetyl,α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(2-naphthyl)acetyl, 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetyl,2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetyl,2-(2-aminothiazol-4-yl)-2-[1-carboxy-1-(3,4-diacetyloxyphenyl)methoxyimino]acetyl,α-(2-oxo-1-imidazolidinecarboxamido)-α-phenylacetyl,α-(3-methylsulfonyl-2-oxo-1-imidazolidinecarboxamino)-α-phenylacetyl,α-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-α-phenylacetyl,α-(4-phenyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetyl,α-[4-(2,4-dichlorophenyl)-2,3-dioxo-1-piperazinecarboxamido]-α-phenylacetyl,α-[(1,4-dihydroxy-4-oxopyridazin-2-yl)carboxamido]-α-phenylacetyl,α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)carboxamido]-α-phenylacetyl,α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)carboxamido]-α-(p-hydroxyphenyl)acetyl,α-[(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)carboxamido]-α-(p-hydroxyphenyl)acetyl,α-(2-aminothiazol-4-yl)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)acetyl,α-(2-aminothiazol-4-yl)-α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)carboxamido]acetyl,α-[(4-oxo-4H-thiopyran-3-yl)carboxamido]-α-phenylacetyl and the like.

In the definition of R⁴, the protecting group for the protected carboxylgroup includes those carboxyl-protecting groups which are conventionallyknown in the penicillin and cephalosporin fields, for example,ester-forming groups which can be removed by catalytic reduction,chemical reduction or treatment under other mild conditions;ester-forming groups which can easily be removed in a living body; andorganosilyl groups, organophosphorus groups and organotin groups whichcan easily be removed by treatment with water or alcohols; and the like.Of these protecting groups, preferable are lower alkyl groups such asmethyl, propyl, tert-butyl and the like; aryl groups; aralkyl groupssuch as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, 3,4-dimethoxybenzyl,4-hydroxy-3,5-di(tert-butyl)benzyl, phenethyl, diphenylmethyl,triphenylmethyl, bis(methoxyphenyl)methyl and the like; phthalidylgroup; halo-lower alkyl groups such as 2-iodoethyl, 2,2,2-trichloroethyland the like; acyloxy-lower alkyl groups such as acetyloxymethyl,propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl,pivaloyloxymethyl, valeryloxymethyl, 1-acetyloxyethyl,1-pivaloyloxyethyl, 1-acetyloxy-n-propyl, 1-pivaloyloxy-n-propyl and thelike; 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl groups such as5-methyl-2-oxo-1,3-dioxol-4-yl-methyl and the like; lower alkoxy-loweralkyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl,isopropoxymethyl and the like; lower alkoxycarbonyloxy-lower alkylgroups such as methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl and the like; etc.

In the definitions of R⁵, R⁶, R⁷ and R⁸, other groups than hydrogenatom, hydroxyl group, carboxyl group, cyano group and sulfo group, maybe substituted by at least one substituent selected from halogen atoms,halo-lower alkyl groups, lower alkyl groups, lower alkoxy groups,carboxy-lower alkoxy groups, lower alkylthio groups, carboxy-loweralkylthio groups, lower alkanoyloxy groups, lower alkoxycarbonyl groups,diphenylmethyloxy-carbonyl groups, aryloxycarboxyl groups, hydroxy-loweralkyl groups, lower alkoxyimino groups, imino group, amino-lower alkylgroups, carboxy-lower alkyl groups, lower alkoxycarbonyl-lower alkylgroups, lower alkoxycarbonylamino groups, nitrobenzyloxycarbonylaminogroups, cyano-lower alkylamino-lower alkyl groups, N,N-di-loweralkylamino groups, lower alkylsulfonyl groups, sulfamoyl-lower alkylgroups, aryl groups, aralkyl groups, carbamoyl group, sulfo group, acylgroups, oxo group, carboxyl group, nitro group, cyano group, aminogroup, hydroxyl group, ureido group, aralkyloxy groups, sulfamoyl group,thioxo group, methylenedioxy group, heterocyclic carbonyl groups,heterocyclic groups and heterocyclicthio groups and the like.

The substituent for each of R⁵, R⁶, R⁷ and R⁸ may further be substitutedby at least one substituent selected from lower alkyl groups, aminogroup, oxo group, hydroxyl group, carbamoyl group, hydroxy-lower alkylgroups, carboxy-lower alkyl groups, N,N-di-lower alkylamino groups,acylamino groups, heterocyclic groups, ureido group,trimethylammonioacetyl groups and guanidino group and the like.

When each of R¹ and R⁴ to R⁸ has an amino group, a hydroxyl group or acarboxyl group, or when each of R¹ and R⁴ to R¹⁰ and the group which Y¹and Y² form when taken together, has an amino group, a hydroxyl group ora carboxyl group, these groups may be protected by a conventionallyknown protecting group. The amino-protecting group includes, forexample, the same amino-protecting groups mentioned in the definition ofR¹ ; the hydroxyl-protecting group includes, for example, formyl,acetyl, benzyl, 4-methoxybenzyl, tetrahydropyranyl, benzyloxycarbonyl,trimethylsilyl and the like. Also, the carboxyl-protecting groupincludes, for example, the same carboxyl-protecting groups as mentionedin the definition of R⁴.

The salts of the penam derivative of general formula [I] includeconventionally known salts in basic groups such as amino group and thelike and in the acidic groups such as carboxyl, sulfo, hydroxyl and thelike.

The salts in the basic group include, for example, salts with mineralacids such as hydrochloric acid, sulfuric acid and the like; salts withorganic carboxylic acids such as formic acid, citric acid,trichloroacetic acid, trifluoroacetic acid and the like; salts withsulfonic acids such as methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesultonicacid and the like, and the salts in the acidic groups include, forexample, salts with alkali metals such as sodium, potassium and thelike; salts with alkaline earth metals such as calcium, magnesium andthe like; ammonium salts; and salts with nitrogen-containing organicbases such as trimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, dicyclohexylamine, procain, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamineand the like.

When the penam derivative of general formula [I] and salts thereof haveisomers (for example, optical isomer, geometric isomer, tautomer and thelike), this invention includes these isomers, and also includes allcrystal forms, hydrates and solvates.

The penam derivatives of general formula [I] and salts thereof may forman intramolecular salts.

An explanation is made below of processes for producing the compound ofthis invention.

The penam derivative of general formula [I] and salt thereof can beproduced by per se known processes or their appropriate combinations,for example, according to the following production routes. ##STR5##

In the above formulas, R, R¹, R², R³, R⁴, R⁷, R⁸ and n are as definedabove. R^(1a) CO-- means the same acyl group as in the definition of R¹,R^(3a) means the same lower alkoxy, lower alkylthio or formamido groupas in the definition of R³, R^(4a) means the same protected carboxylgroup as in the definition of R⁴, R¹¹ CO-- means the same substitutedacyl or unsubstituted group as in the definitions of R⁵ and R⁶, R¹² SO₂-- means the same substituted or unsubstituted lower alkylsulfonyl groupas in the definitions of R⁵ and R⁶, R¹³ means a hydrogen atom or thesame substituent for the carbamoyl group in the definitions of R⁵ and R⁶and X¹ means a removable group.

Incidentally, the penam derivatives of general formulas [Ib] and [IV]are important intermediates for producing the compound of thisinvention.

The salts of the compounds of general formulas [Ia], [Ib], [Ic] and [IV]include the same salts as mentioned as to the salts of the compound ofgeneral formula [I].

The salt of the compound of general formula [VIII] includes salts withalkali metals such as sodium, potassium and the like and salts withalkaline earth metals such as calcium, magnesium and the like.

The removable group of X¹ includes halogen atoms; lower alkylsulfonyloxygroups such as methylsulfonyloxy, ethylsulfonyloxy and the like;arylsulfonyloxy groups such as phenylsulfonyloxy, toluenesulfonyloxy andthe like; acyloxy groups such as acetyloxy, benzoyloxy and the like;etc.

The reactive derivatives in the amino group of the compound of generalformula [Ib] or [IV] includes those reactive derivatives which are oftenused in acylation such as Schiff bases (isomer of imino type or itsenamine type) produced by reaction of the compound of general formula[Ib] or [IV] or a salt thereof with a carbonyl compound such as analdehyde, a ketone or the like; silyl derivatives produced by reactionof the compound of general formula [Ib] or [IV] or a salt thereof withan organosilyl compound such as N,O-bis(trimethylsilyl)acetamide,trimethylsilylacetamide, trimethylsilyl chloride or the like; phosphorusderivatives produced by reaction of the compound of general formula [Ib]or [IV] or a salt thereof with a phosphorus compound such as2-chloro-1,3,2-dioxaphosphorane,2-chloro-4-methyl-1,3,2-dioxaphosphorane,2-chloro-1,3,2-dioxaphosphorinane, chlorodiethyloxyphosphine,chlorodiethylphosphine, phosphorus trichloride or the like, or tinderivatives produced by reaction of the compound of general formula [Ib]or [IV] or a salt thereof with a tin compound such aschlorotriethylstannane or the like.

The reactive derivatives in the carboxylic acid of general formula [III]includes specifically acid halides, acid anhydrides; mixed anhydrideswith monoalkyl carbonates such as monoethyl carbonate, monoisobutylcarbonate and the like; mixed anhydrides with optionallyhalogen-substituted lower alkanoic acids such as pivalic acid,trichloroacetic acid and the like; active acid amides such asN-acylimidazole, N-acylbenzoylamide, N,N'-dicyclohexyl-N-acylurea,N-acylsulfonamide and the like; active esters such as cyanomethyl ester,substituted phenyl ester, substituted benzyl ester, substituted thienylester and the like; and reactive derivatives produced by reaction of thecarboxylic acid of general formula [III] with a Vilsmeier reagent(obtained by reacting an acid amide such as N,N-dimethylformamide orN,N-dimethylacetamide with a halogenating agent such as phosgene,thionyl chloride, phosphorus trichloride, phosphorus tribromide,phosphorus oxychloride, phosphorus pentachloride, trichloromethylchloroformate, oxalyl chloride or the like); etc.

A more detailed explanation is further made below of the process forproducing the compound of general formula [I] referring to theabove-mentioned production route.

(1) Ring closure

The compound of general formula [Ia] or its salt can be produced bysubjecting a compound of general formula [II] to ring closure reactionin the presence of a base.

The solvent to be used in this reaction may be any solvent as far as itdoes not adversely affect the reaction, and includes, for example,halogenated hydrocarbons such as methylene chloride, chloroform and thelike; ethers such as tetrahydrofuran and the like; nitriles such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxideand the like; phosphoric acid amides such as hexamethylphosphoric acidtriamide and the like; etc. These solvents may be used alone or inadmixture of two or more.

The base to be used in this reaction includes inorganic and organicbases, for example, alkali hydroxides such as sodium hydroxide,potassium hydroxide and the like; alkali hydrogencarbonates such assodium hydrogencarbonate and the like; alkali carbonates such as sodiumcarbonate and the like; metal hydrides such as sodium hydride, calciumhydride and the like; alkali acetate such as sodium acetate and thelike; potassium tert-butoxide; diethylamine; triethylamine; lithiumdiisopropylamide; lithium bis(trimethylsilyl)amide; cyclohexylamine;pyridine; 2,6-lutidine; N-methylpiperidine; N-methylmorpholine;tetramethylguanidine; 1,8-diazabicyclo[5.4.0]undec-7-ene;methylmagnesium bromide; 2,4,6-trimethylphenylmagnesium bromide; and thelike.

The amount of the base used is 1-5 moles, preferably 1.0 to 1.5 moles,per mole of the compound of general formula [II].

The reaction temperature and reaction time are not critical; however,usually the reaction may be carried out at -60° to 30° C., preferably-40° to 5° C., for 5 minutes to 2 hours.

The compound of general formula [Ia] or its salt thus obtained may beused as it is without being isolated in the subsequent reaction.

In the above reaction, when the compound of general formula [II] hasbonded thereto a group having acidic proton such as an amido group orthe like, a silylating agent, for example,N,O-bis(trimethylsilyl)acetamide or the like may be added to increasethe yield.

(2) Deacylation

The compound of general formula [Ib] or its salt can be obtained bysubjecting a compound of general formula [Ia] or its salt toconventional deacylation (for example, reacting the compound of generalformula [Ia] or its salt with phosphorus pentachloride to form animinochloride, then reacting it with an alcohol to form an iminoetherand thereafter hydrolyzing the same).

This deacylation can be carried out by a deacylation method which isconventionally used in the penicillin and cephalosporin fields, forexample, the method disclosed in, for example, Recl. Trav. Chim.Pays-Bas, vol. 89, p. 1081 (1973) or Japanese Patent Application KokokuNo. 38,954/1980 or a method similar thereto.

The compound of general formula [Ib] or its salt obtained by the abovereaction can be used as it is without being isolated in the subsequentreaction.

(3) (i) Acylation

The compound of general formula [Ia] or its salt can be produced byreacting a compound of general formula [Ib] or its salt or a reactivederivative in the amino group thereof with a carboxylic acid of generalformula [III] or a reactive derivative thereof.

This acylation may be usually carried out in the presence or absence ofa base in an appropriate solvent.

The solvent to be used in this reaction may be any solvent as far as itdoes not adversely affect the reaction, and includes, for example,halogenated hydrocarbons such as methylene chloride, chloroform and thelike; ethers such as tetrahydrofuran, dioxane and the like; amides suchas N,N-dimethylformamide, N,N-dimethylacetamide and the like; ketonessuch as acetone and the like; water; and the like. These solvents may beused alone or in admixture of two or more.

The base which is optionally used in the above reaction includes thesame bases as mentioned in (1) above.

When the compound of general formula [III] is used in the form of a freeacid, an appropriate condensing agent is used. Such a condensing agentincludes, for example, N,N'-di-substituted carbodiimide such asN,N'-dicyclohexylcarbodiimide or the like; 1,1'-carbonyldiimidazole;dehydrating agents such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, phosphorusoxychloride, alkoxyacetylene or the like; and 2-halogenopyridinium saltssuch as 2-chloropyridinium methyliodide, 2-fluoropyridinium methyliodideand the like.

The amount of the carboxylic acid of general formula [III] or itsreactive derivative used is 1.0 to 1.5 moles per mole of the compound ofgeneral formula [Ib] or its salt or reactive derivative in the aminogroup thereof.

The reaction temperature and reaction time are not critical; however,the reaction may be usually carried out at -50° to 40° C. for 10 minutesto 48 hours.

(ii) Alternatively, the compound of general formula [Ia] or its salt canalso be produced by reacting a compound of general formula [IV] or itssalt or a reactive derivative in the amino group thereof with a compoundof general formula [V] or a compound of general formula [VI] or [VII] ortheir salts or reactive derivatives thereof, or a compound of generalformula [VIII] or its salt or sulfur trioxide.

These reactions can be carried out by a method known per se, forexample, the acylation mentioned in (3)(i) above, the method describedin Advanced Organic Chemistry, Reactions Mechanisms and Structures,second edition, pp. 382-388 and 823 (1977), the Journal of Antibiotics,vol. 31, pp. 546-560 (1978) and id., vol. 42, p. 1418 (1988) and Journalof American Chemical Society, pp. 5349-5351 (1956) and the like or amethod similar thereto.

In each of the above-mentioned production routes when the compounds havea hydroxyl group, an amino group or a carboxyl group, it is possible topreviously protect these groups with a conventional protective group andto remove, after the reaction, the protective group, if necessary,according to a per se known method.

The compound of general formula [Ic] or its salt in which R^(3a) is alower alkoxy group can be derived from a compound of general formula[Ia] or its salt in a conventional manner. The compound of generalformula [Ic] or its salt in which R^(3a) is a lower alkylthio group canbe obtained by protecting the amino group of the compound of generalformula [Ib] or its salt with, for example, the above-mentionedamino-protecting group, thereafter introducing a lower alkylthio groupthereinto and, if necessary, removing the protecting group andthereafter subjecting the product to the acylation mentioned in (3)(i)above. The compound of general formula [Ic] or its salt in which R^(3a)is a formamido group can be obtained by formamidation of, for example, acompound of general formula [Ic] or its salt in which R^(3a) is a loweralkylthio group. The introduction of a lower alkylthio group and theformamidation can be carried out by the method described in, forexample, Japanese Patent Application Kokai (Laid-Open) No. 38,288/1983or a method similar thereto.

The compounds of general formulas [Ia], [Ib] and [Ic] in which R⁴ is acarboxyl group can be obtained by subjecting compounds of generalformulas [Ia], [Ib] and [Ic] in which R⁴ is a protected carboxyl group,respectively, to conventional removal of carboxyl-protecting group.

The compound of this invention thus obtained can be converted into othercompounds of this invention by subjecting the former to conventionallyknown reactions or their appropriate combinations, for example,esterification, hydrolysis, addition reaction, acylation, oxidation,reduction, cyclization, halogenation, alkylation, amidation,alkylidenation, Wittig reaction and the like. These reactions can becarried out by the methods specifically described in, for example, Russ.Chem. Revs., vol. 33, pp. 66-77 (1964) and the like or a method similarthereto.

When there are isomers of the compound of general formula [Ia] or itssalt; the compound of general formula [II]; the compound of generalformula [Ib] or [IV] or its salt or reactive derivative in the aminogroup thereof; the carboxylic acid of general formula [III] or [VI] orits reactive derivative; and the compound of general formula [VII] orits reactive derivative (for example, optical isomers, geometricisomers, tautomers and the like), all of these isomers can be used. Inaddition, all crystal forms, hydrates and solvates can be used.

The compound of general formula [I] or its salt of this invention thusobtained can be isolated and purified by a conventional method such asextraction, crystallization, distillation, chromatography and the like.

Next, an explanation is made of a process for producing the compound ofgeneral formula [II] and the compound of general formula [IV] or itssalt or reactive derivative in the amino group thereof which is thestarting material for producing the compound of this invention.

The compound of general formula [IV] or its salt or reactive derivativein the amino group thereof can be obtained by a method known per se suchas the method described in, for example, Tetrahedron Letters, pp.375-378 and 4917-4920 (1972) or a method similar thereto.

The compounds of general formula [II] can be obtained by per se knownprocesses or their appropriate combinations. For example, they can beproduced according to the following production route. ##STR6##

In the above formulas, R², R³, R^(1a) CO--, R^(4a), X¹ and n are asdefined above; R^(a) represents an amino group, a group of the formula,--NHR⁵ or --NR⁵ 6 in which R⁵ and R⁶ are as defined above, or a group ofthe formula, --N═CR⁷ R⁸ in which R⁷ and R⁸ are as defined above; X²means the same removable group as defined as to X¹.

The salts of the compounds of general formulas [IX], [X], [XI], [XII]and [XIII] include the same salts as mentioned as to the compound ofgeneral formula [I].

The reactive derivatives in the amino group of the compound of generalformula [XIII] and its salt include the same reactive derivatives asmentioned as to the compounds of general formulas [Ib] and [IV] andtheir salts.

Next, a more detailed explanation is made of the above production routefor producing the compound of general formula [II].

In the above production route, the reaction with the carboxylic acid ofgeneral formula [III] or its reactive derivative and the deacylation canbe carried out in the same manners as explained in (2) Deacylation and(3)(i) Acylation above.

The compound of general formula [II] can be produced by reacting acompound of general formula [XII] or its salt with a halogenating agent,a sulfonylating agent or an acylating agent in the presence or absenceof a base.

This reaction is preferably conducted under anhydrous conditions, andthe solvent to be used may be any solvent as far as it does notadversely affect the reaction. The solvent includes, for example,halogenated hydrocarbons such as methylene chloride, chloroform and thelike; ethers such as tetrahydrofuran and the like; nitriles such asacetonitrile and the like; and amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like. These solvents may be used alone orin admixture of two or more.

The halogenating agent to be used in the reaction includes, for example,thionyl halides such as thionyl chloride, thionyl bromide and the like;the sulfonylating agent to be used in the reaction includes, forexample, lower alkanesulfonyl chlorides such as methanesulfonyl chlorideand arylsulfonyl chlorides such as p-toluenesulfonyl chloride; and theacylating agent to be used in the reaction includes, for example, acidanhydrides such as acetic anhydride and acid chlorides such as acetylchloride, benzoyl chloride and the like.

The base which is optionally used in the above reaction includes thesame inorganic and organic bases as mentioned in (1) Ring closure.

Each of the amounts of the halogenating agent, sulfonylating agent andacylating agent used and the amount of the base optionally used is 1 to5 moles, preferably 1.0 to 1.2 moles, per mole of the compound ofgeneral formula [XII] or its salt.

The reaction temperature and reaction time are not critical; however,the reaction may be carried out at -30° to 30° C., for 5 minutes to 1hour.

The compounds of general formulas [IX], [XI] and [XII] and their saltscan be produced according to the method described in, for example,Japanese Patent Application Kokai (Laid-Open) No. 183,588/1988 or amethod similar thereto.

Further, the compound of general formula [IIa] can be converted into acompound of general formula [IIa] in which the group corresponding toR^(a) is an amino group by subjecting the former to a generally knownmethod such as removal of amino-protecting group, reduction or the like.

In each of the above-mentioned production routes, when the compoundshave a hydroxyl group, an amino group or a carboxyl group, it ispossible to previously protect these groups with a conventionalprotective group and to remove, after the reaction, the protectivegroup, if necessary, according to a per se known method.

When the compounds of general formulas [IX], [X], [XI] and [XII] andtheir salts and the compound of general formula [XIII], its salt andreactive derivatives in the amino group thereof have isomers (forexample, optical isomers, geometric isomers, tautomers and the like),all of these isomers may be used. Also, all crystal forms, hydrates andsolvates may be used.

The compounds of general formulas [IX], [XI], [XII] and [XIII] thusobtained can be used as they are without being isolated in thesubsequent reactions.

When the compound of this invention is used as a drug, it may be mixedappropriately with an excipient which is usually used in preparation, apreparation adjuvant such as pharmaceutically acceptable carrier or thelike. The compound can be administered orally or parenterally in theform of a tablet, soft or hard capsule, powder, syrup, granule, finegranule, pill, suspension, emulsion, solution, suppository, ointment orsubcutaneous, intramuscular, intravenous or drip infusion.

The administration route, does and number of administrations of thecompound of this invention can be appropriately varied depending uponthe age, weight and symptom of a patient, and usually, the compound maybe administered to an adult patient orally or parenterally (for example,by injection, drip, rectal administration or the like) in an amount of 1to 250 mg/kg/day in one to several portions.

Next, the antibacterial activities of representative compounds of thisinvention are explained.

1. Antibacterial activity Test Method

According to Chemotherapy, vol. 29, No. 1, pp. 76-79 (1981), bacteriumwas cultured in peptone broth manufactured by Eiken Kagaku K.K. at 37°C. for 20 hours to prepare a bacterial solution of 10⁸ cells/ml, and oneloopful of the bacterial solution was inoculated into Heart Infusionagar medium (manufactured by Eiken Kagaku K.K.) containing a drug,cultured at 37° C. for 20 hours, after which growth of bacterium wasobserved. The minimum concentration at which the growth of bacterium wasprevented was indicated as MIC (μg/ml).

The test compounds used are shown in Table 1 and the results obtainedare shown in Table 2.

The symbols used in Table 1 have the following meanings:

Ac: acetyl group, Me: methyl group, Et: ethyl group.

R^(1a) and R in Table 1 refer to those in the following formula for thetest compounds:

                                      TABLE 1                                     __________________________________________________________________________     ##STR7##                                                                             Substituent                                                           Compound No.                                                                          R.sup.1a          R                                                   __________________________________________________________________________     1                                                                                     ##STR8##                                                                                        ##STR9##                                            2      "                                                                                                ##STR10##                                           3      "                                                                                                ##STR11##                                           4      "                                                                                                ##STR12##                                           5      "                                                                                                ##STR13##                                           6      "                                                                                                ##STR14##                                           7      "                                                                                                ##STR15##                                           8                                                                                     ##STR16##                                                                                       ##STR17##                                           9      "                 NCHCO.sub.2 Na                                      10      "                 NCHCHCH.sub.2                                       11      "                 NCHCHCHCO.sub.2 Na                                  12      "                 NCHCHCHCH.sub.2 SO.sub.3 Na                         13                                                                                     ##STR18##                                                                                       ##STR19##                                          14      "                                                                                                ##STR20##                                          15      "                                                                                                ##STR21##                                          16      "                 NHSO.sub.3 Na                                       17      "                                                                                                ##STR22##                                          18      "                 NCHCHCH.sub.2                                       19      "                 NCHCCH                                              20                                                                                     ##STR23##                                                                                       ##STR24##                                          21                                                                                     ##STR25##        "                                                   22                                                                                     ##STR26##        "                                                   23                                                                                     ##STR27##                                                                                       ##STR28##                                          24      "                                                                                                ##STR29##                                          25                                                                                     ##STR30##        "                                                   26                                                                                     ##STR31##                                                                                       ##STR32##                                          27                                                                                     ##STR33##        "                                                   28                                                                                     ##STR34##                                                                                       ##STR35##                                          29                                                                                     ##STR36##        "                                                   30                                                                                     ##STR37##        "                                                   31                                                                                     ##STR38##        NCHCHCHCN                                           32      "                                                                                                ##STR39##                                          33      "                                                                                                ##STR40##                                          34                                                                                     ##STR41##                                                                                       ##STR42##                                          35                                                                                     ##STR43##                                                                                       ##STR44##                                          36                                                                                     ##STR45##        "                                                   37                                                                                     ##STR46##                                                                                       ##STR47##                                          38                                                                                     ##STR48##        "                                                   39                                                                                     ##STR49##        "                                                   40                                                                                     ##STR50##        "                                                   41                                                                                     ##STR51##        "                                                   42                                                                                     ##STR52##        "                                                   43      "                                                                                                ##STR53##                                          44                                                                                     ##STR54##        NHSO.sub.2 NH.sub.2                                 45                                                                                     ##STR55##        NHCOCHCH.sub.2                                      46                                                                                     ##STR56##                                                                                       ##STR57##                                          47                                                                                     ##STR58##                                                                                       ##STR59##                                          48                                                                                     ##STR60##        NCHCHCHCO.sub.2 Na                                  49      "                 NCHCHCH.sub.2                                       50                                                                                     ##STR61##                                                                                       ##STR62##                                          51      Control compound                                                      __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        MIC (μ g/ml)                                                               Strain   Compound No.                                                         ______________________________________                                                 1       2       3     4     5     6                                  ______________________________________                                        E. coli TK-3*                                                                          0.39    0.39    0.78  6.25  3.13  3.13                               S. marcescens                                                                          0.1     0.39    0.78  6.25  3.13  1.56                               W-8*                                                                          ______________________________________                                                 7       8       9     10    11    12                                 ______________________________________                                        E. coli TK-3*                                                                          12.5    3.13    25    0.1   0.2   0.78                               S. marcescens                                                                          6.25    1.56    12.5  0.05  0.1   0.1                                W-8*                                                                          ______________________________________                                                 13      14      15    16    17    18                                 ______________________________________                                        E. coli TK-3*                                                                          12.5    3.13    12.5  12.5  1.56  ≦0.05                       S. marcescens                                                                          3.13    3.13    12.5  12.5  1.56  0.1                                W-8*                                                                          ______________________________________                                                 19      20      21    22    23    24                                 ______________________________________                                        E. coli TK-3*                                                                          ≦0.05                                                                          0.78    0.39  6.25  3.13  25                                 S. marcescens                                                                          ≦0.05                                                                          0.78    0.39  12.5  3.13  12.5                               W-8*                                                                          ______________________________________                                                 25      26      27    28    29     30                                ______________________________________                                        E. coli TK-3*                                                                          6.25    ≦0.1                                                                           1.56  6.25  6.25  6.25                               S. marcescens                                                                          12.5    0.39    --    3.13  3.13  1.56                               W-8*                                                                          ______________________________________                                                 31      32      33    34    35    36                                 ______________________________________                                        E. coli TK-3*                                                                          0.2     1.56    0.39  0.2   1.56  12.5                               S. marcescens                                                                          0.1     0.78    0.2   0.39  0.78  1.56                               W-8*                                                                          ______________________________________                                                 37      38      39    40    41    42                                 ______________________________________                                        E. coli TK-3*                                                                          0.78    1.56    3.13  3.13  3.13  0.2                                S. marcescens                                                                          0.2     0.78    0.78  0.78  1.56  0.39                               W-8*                                                                          ______________________________________                                                 43      44      45    46    47    48                                 ______________________________________                                        E. coli TK-3*                                                                          0.2     6.25    3.13  12.5  0.78  0.1                                S. marcescens                                                                          0.2     6.25    3.13  6.25  6.25  0.1                                W-8*                                                                          ______________________________________                                                     49        50        51                                           ______________________________________                                        E. coli TK-3*                                                                              ≦0.05                                                                            0.39      >200                                         S. marcescens W-8*                                                                         ≦0.05                                                                            0.1       >200                                         ______________________________________                                         Note:                                                                         *means that β-lactamaseproducing bacteria.                                Control compound: Sodium salt of                                             (3R,5R,6R)3-carboxy-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxami    o)-α-phenylacetamido]-3-(3-methyl-2-oxoimidazolidin-1-yl)-7-oxo-4-th    a-1-azabicyclo[3.2.0]heptane (Compound No. 72 in Example 9 of Japanese         Patent Application Kokai (LaidOpen) No. 183,588/1988).                   

As is clear from the above results, the compound of this invention canbe utilized as an antibacterial agent.

This invention is described in detail below by way of Reference Examplesand Examples. However, this invention is not restricted to theseExamples.

In the Examples, there were used, as a carrier in column chromatography,Kieselgel 60, Art. 7734 manufactured by Merck Co.; as a carrier inreversed phase column chromatography, LC-SORB SP-B-ODS manufactured byChemco Co.; as a carrier in ion exchange column chromatography,Amberlite IR-120B manufactured by Rohm and Haas Co. The mixing ratio inmixed solvent is by volume in all cases.

The symbols used in Reference Examples and Examples have the followingmeanings.

Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, Ac: acetylgroup, Ph: phenyl group, Bzl: benzyl group, PNB: p-nitrobenzyl group,PMB: p-methoxybenzyl group, DPM: diphenylmethyl group

The wave number of IR indicates the absorption of carbonyl.

The D and L in each of Reference Example 3 and Examples 5, 13, 24, 26,35, 36, 39, 40, 41, 42, 43, 44, 45 and 48 are by estimate.

Reference Example 1

The reaction represented by the following production route ##STR63## [Rand n have the same meanings as given above, and R¹⁴ represents the samecarboxyl-protecting group as described for R⁴ ] was conducted inaccordance with the method described in Japanese Patent ApplicationKokai (Laid-Open) No. 183588/1988, to obtain compounds shown in Table 3.

In Table 3, R and R¹⁴ each show a substituent of the following formula,and n is 1 or 2 as shown in Table 3.

                  TABLE 3                                                         ______________________________________                                         ##STR64##                   [XIa]                                             ##STR65##                   [XIIc]                                                                IR(KBr) cm.sup.-1 :                                                                     Com-   Com-                                                                   pound  pound                                   R                R.sup.14                                                                              n     [XIa]  [XIIc]                                  ______________________________________                                         ##STR66##       PNB     1     1750, 1710                                                                           1750, 1700                               ##STR67##       "       "     1735, 1680                                                                           1750, 1690                               ##STR68##       "       "     1745, 1695                                                                           1760, 1750, 1715, 1680                   ##STR69##       "       "     1740, 1700                                                                           1750, 1710, 1670                        NCHCH.sub.2 Cl   "       "     --     1760,                                                                         1740,                                                                         1720,                                                                         1660                                     ##STR70##       "       "     1750, 1680                                                                           1760, 1750, 1700                         ##STR71##       DPM     1     1755, 1725                                                                           1760, 1740, 1700, 1670                   ##STR72##       DPM     1     1750, 1705                                                                           1770, 1740, 1710, 1680                   ##STR73##       PNB     2     1755, 1680, 1660                                                                     1750, 1670                               ##STR74##       DPM     1     1750, 1700                                                                           1770, 1740, 1705, 1670, 1640             ##STR75##       "       "     1760, 1700                                                                           --                                       ##STR76##       "       "     1745, 1710                                                                           --                                      ______________________________________                                    

Reference Example 2

15 g of (2-chloro-4,5-diacetoxyphenyl)acetic acid was dissolved in 75 mlof methylene chloride. Thereto was added 9.67 g of a sulfurtrioxide-dioxane complex with ice cooling. The mixture was stirred atroom temperature for 12 hours. Then, there were added, with ice cooling,225 ml of ethanol and 18.75 ml of an aqueous solution containing 16.38 gof sodium acetate trihydrate. The mixture was stirred at roomtemperature for 1 hour. 150 ml of ethanol was added and the mixture wasstirred at the same temperature for 3 hours. The resulting mixture wascooled to 5°-10° C. The precipitates were collected by filtration anddried to obtain crude crystals of disodium salt ofDL-α-(2-chloro-4,5-diacetoxyphenyl)-α-sulfoacetic acid. Then, the crudecrystals were suspended in 155 ml of methanol, and the suspension wasstirred at room temperature for 10 minutes. The insolubles were removedby filtration. To the filtrate was added 15.5 ml of an aqueous solutioncontaining 10.24 g of sodium acetate trihydrate, and the mixture wasstirred at 30° C. for 8 hours. The resulting crystals were collected byfiltration, washed with 16 ml of methanol, and dried under reducedpressure to obtain 11.10 g (yield: 65.0%) of disodium salt ofDL-α-(2-chloro 4,5-dihydroxyphenyl)-α-sulfoacetic acid.

IR (KBr) cm⁻¹ : 1610, 1580

Reference Example 3

(1) 50 g of disodium salt ofDL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid was dissolved in400 ml of water. Thereto was added an ion exchange resin (AmberliteIR-120B, H⁺ type) to adjust the pH to 2.1. The ion exchange resin wasremoved by filtration and washed twice each with 100 ml of water. Thefiltrate and the washings were combined. To the resulting solution wasadded 40.1 g of cinchonidine at 90°-95° C. in 30 minutes. The mixturewas stirred at the same temperature for 3 hours and then allowed tostand overnight at room temperature. The resulting crystals werecollected by filtration, washed with water and acetone in this order,dried under reduced pressure. The crystals obtained were suspended in300 ml of ethanol and heated to obtain a solution. Thereto was added 600ml of hot water of about 60° C., and the mixture was allowed to standovernight at room temperature. The resulting crystals were collected byfiltration, washed with water and acetone in this order, and dried underreduced pressure to obtain 51.2 g (yield 38.8%) of dicinchonidine saltof α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid.

IR (KBr) cm⁻¹ : 1655, 1590, 1570

(2) 20.0 g of dicinchonidine salt ofα-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid was dissolved in amixed solvent consisting of 40 ml of methanol and 40 ml of chloroform.The resulting solution was added to a mixture of 30 ml of an aqueoussolution containing 4.60 g of potassium hydrogencarbonate and 40 ml ofchloroform. The resulting mixture was stirred for 1.5 hours at roomtemperature. The aqueous layer was separated, washed twice each with 40ml of chloroform, and mixed with an ion exchange resin (AmberliteIR-120B, H⁺ type) to adjust the pH to 2. The ion exchange resin wasremoved by filtration and washed with 30 ml of water. The filtrate andthe washings were combined, and concentrated to about 30 ml underreduced pressure. The residue was subjected to ion exchange columnchromatography (H⁺ type, eluant: water). The eluate was concentratedunder reduced pressure. The residue was dissolved in 20 ml ofacetonitrile. Thereto was dropwise added 8.48 ml of tri-n-butylamine,and the mixture was stirred for 30 minutes at the same temperature. Theresulting crystals were collected by filtration and washed withacetonitrile and diethyl ether, and dried under reduced pressure toobtain 10.2 g (yield: 67.7%) of di-tri-n-butylamine salt ofD-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid.

IR (KBr) cm⁻¹ : 1605

[α]_(D) ²⁰ : -3.5° (C=3.0, methanol)

Reference Example 4

4.0 g of disodium salt ofDL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid was subjected toion exchange column chromatography (H⁺ type, eluant: water). The eluatewas concentrated under reduced pressure. The residue was dissolved in 20ml of acetonitrile. Thereto was added dropwise 5.72 ml oftri-n-butylamine with ice cooling. The mixture was stirred at the sametemperature for 30 minutes. The resulting crystals were collected byfiltration and washed with acetonitrile and diethyl ether, and driedunder reduced pressure to obtain 5.0 g (yield: 62.5%) ofdi-tri-n-butylamine salt ofDL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid.

IR (KBr) cm⁻¹ : 1610

EXAMPLE 1

In 420 ml of anhydrous tetrahydrofuran was dissolved 30.00 g of(3R,4R)-4-[1-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-1-(p-nitrobenzyloxycarbonyl)methylthio]-1-hydroxymethyl-3-phenylacetamidoazetidin-2-one.To the solution were added, with ice cooling, 6.72 ml of 2,6-lutidineand 3.95 ml of thionyl chloride in this order. The mixture was stirredat room temperature for 10 minutes. The insolubles were removed byfiltration. The solvent was removed by distillation under reducedpressure. The residue was dissolved in 600 ml of anhydroustetrahydrofuran. To the solution was added 13.6 ml ofN,O-bis(trimethylsilyl)acetamide. The mixture was stirred at roomtemperature for 15 minutes and cooled to -60° C. To the reaction mixturewere added, at -40° C. or below, 40.4 ml of hexamethylphosphorictriamide and 69.6 ml of tetrahydrofuran solution containing lithiumbis(trimethylsilyl)amide (0.8 mmol/ml), in this order. The temperatureof the mixture was elevated to -15° C. in 1 hour. To the reactionmixture was added 3.16 ml of acetic acid while maintaining thetemperature at -15° C. The mixture was added to a mixed solventconsisting of 500 ml of water and 500 ml of ethyl acetate. The resultingmixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organiclayer was separated, washed with diluted hydrochloric acid of pH 2.0,mixed with 200 ml of water, and adjusted to pH 7.0 with an aqueoussodium hydrogencarbonate solution. The organic layer was separated,washed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue was purifiedby column chromatography (eluant: n-hexane/ethyl acetate=1/1 to 2/1) toobtain 13.32 g (yield: 45.7%) of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1720, 1660

The compounds shown in Table 4 were obtained in the same manner.

In Table 4, R and R¹⁴ each show a substituent of the following formula,and n is 1 or 2 as shown in Table 4.

                  TABLE 4                                                         ______________________________________                                         ##STR77##                                                                    R                 R.sup.14                                                                              n      IR(KBr) cm.sup.-1 :                          ______________________________________                                         ##STR78##        PNB     1      1780, 1710, 1660                              ##STR79##        "       "      1780, 1720, 1660                              ##STR80##        "       "      1780, 1720, 1670                             NCHCH.sub.2 Cl    "       "      1780, 1720, 1660                              ##STR81##        "       "      1780, 1730, 1705, 1670                        ##STR82##        DPM     "      1780, 1710, 1665                              ##STR83##        "       "      --                                            ##STR84##        DPM     1      1790, 1740, 1730, 1680                        ##STR85##        "       "      1790, 1740, 1725, 1680                        ##STR86##        "       "      1785, 1735, 1690, 1670                        ##STR87##        PNB     2      1780, 1740, 1680, 1665                       ______________________________________                                    

EXAMPLE 2

In 132 ml of methylene chloride was dissolved 6.6 g of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -60° C. Thereto were added 4.66 ml ofN,N-dimethylaniline and 3.3 g of phosphorus pentachloride. The mixturewas stirred at -40° to -20° C. for 1 hour and cooled to -60° C. To thereaction mixture was added 13.8 ml of anhydrous methanol. Thetemperature of the mixture was elevated to 0° C. in 30 minutes and mixedwith 66 ml of water. The resulting mixture was stirred for 15 minuteswith ice cooling. The resulting crystals were collected by filtrationand suspended in a mixed solvent consisting of 50 ml of water and 100 mlof methylene chloride. The suspension was adjusted to pH 7.5 with asaturated aqueous sodium hydrogencarbonate solution. The organic layerwas separated and dried over anhydrous magnesium sulfate. The solventwas removed by distillation under reduced pressure to obtain 4.5 g(yield: 84.0%) of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabioyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1720

The compounds shown in Table 5 were obtained in the same manner.

In Table 5, R and R¹⁴ each show a substituent of the following formula.

                  TABLE 5                                                         ______________________________________                                         ##STR88##                                                                    R               R.sup.14   IR(KBr) cm.sup.-1 :                                ______________________________________                                         ##STR89##      DPM        1775, 1725, 1710                                    ##STR90##      PNB        1780, 1740, 1705                                   "               DPM        1775, 1730, 1710                                   NCHCH.sub.2 Cl  PNB        1775, 1735, 1710                                   ______________________________________                                    

EXAMPLE 3

(1) In a mixed solvent consisting of 200 ml of methylene chloride and 70ml of methanol was dissolved 13.2 g of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto were added 10.3 g of 2,4-dinitrophenylhydrazine and 9.83 g ofp-toluenesulfonic acid monohydrate in this order. The mixture wasstirred at room temperature for 1.5 hours. The insolubles were removedby filtration. The insolubles were washed with a mixed solventconsisting of 60 ml of methylene chloride and 20 ml of methanol. Thewashings and the filtrate obtained previously were combined, and mixedwith 50 ml of water. The aqueous layer was separated. The organic layerwas mixed with 30 ml of water and adjusted to pH 1.2 with 6Nhydrochloric acid. The aqueous layer was separated. This aqueous layerand the aqueous layer obtained previously were combined and adjusted topH 7 with sodium hydrogencarbonate. Thereto was added sodium chloride tosaturation. Then, the aqueous layer was extracted with 150 ml ofmethylene chloride. The aqueous layer was further extracted 7 times eachwith 50 ml of methylene chloride. The extracts were combined with theorganic layer obtained previously, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue was purified by column chromatography (eluant:chloroform/methanol=50/1 to 15/1) to obtain 8.93 g (yield: 81.8%) of(3R,5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1775, 1740, 1700

NMR (CDCl₃ /D₂ O) δ: 3.29(1H, dd, J=1 Hz, J=13 Hz), 3.53(4H, s),4.54(1H, dd, J=1 Hz, J=4 Hz), 4.88(1H, d, J=13 Hz), 5.30(2H, s),5.45(1H, d, J=4 Hz), 7.56(2H, d, J=9 Hz), 8.24(2H, d, J=9 Hz).

In the same manner was obtained(3R,5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1775, 1720, 1700

(2) In a mixed solvent consisting of 30 ml of water and 30 ml ofmethanol was suspended 5.00 g of(3R,5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To suspension was added 2.96 ml of concentrated hydrochloric acid withwater cooling. To the resulting solution was added 1.36 g of sodiumcyanate in 10 minutes, and the mixture was stirred at room temperaturefor 30 minutes. The reaction mixture was filtered. To the filtrate wereadded 50 ml of ethyl acetate and 50 ml of water. The aqueous layer wasseparated. The organic layer was extracted three times each with 30 mlof water. The extracts were combined with the aqueous layer obtainedpreviously. The combined aqueous solution was adjusted to pH 6.9 withsodium hydrogencarbonate. The solvent was removed by distillation underreduced pressure. The residue was dehydrated by four times of azeotropywith ethanol. To the resulting residue was added a mixed solventconsisting of 50 ml of methylene chloride and 10 ml of methanol. Theinsolubles were removed by filtration. The filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/methanol=10/1 to 5/1) to obtain 4.29g (yield: 77.9%) of(3R,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1775, 1720, 1680

NMR (d₆ -DMSO/D₂ O) δ: 3.15-3.80(5H, m), 4.57(1H, d, J=4 Hz), 4.59(1H,d, J=13 Hz), 5.27(2H, s). 5.48(1H, d, J=4 Hz), 7.65(2H, d, J=9 Hz),8.23(2H, d. J=9 Hz).

In the same manner was obtained(3R,5R,6R)-6-amino-3-diphenylmethyloxycarbonyl-7-oxo-3-(2-oxo-3-uriedoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1720, 1680

In the same manner in hydrous tetrahydrofuran, there was obtained(3R,5R,6R)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-6-[DL-α-(p-nitrobenzyloxycarbonyl)-α-phenylacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1775, 1720, 1680

EXAMPLE 4

(1) In 8 ml of methylene chloride was dissolved 300 mg of(3R,5R,6R)-3-{3-(2-furfurylideneamino)-2-oxoimidazolidin-1-yl}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -50° C. Thereto were added 0.18 ml ofN,N-dimethylaniline and 141 mg of phosphorus pentachloride in thisorder. The mixture was stirred at -40° to -20° C. for 1 hour and cooledto -60° C. To the reaction mixture was added 1.4 ml of anhydrousmethanol, and the resulting mixture was stirred at -10° to 0° C. for 30minutes. 5 ml of water was added to the reaction mixture. The resultingmixture was stirred for 10 minutes with ice cooling and adjusted to pH7.5 with a saturated aqueous sodium hydrogencarbonate solution. Theorganic layer was separated, washed with water and a saturated aqueoussodium chloride solution in this order, and dried over anhydrousmagnesium sulfate to obtain a methylene chloride solution of(3R,5R,6R)-6-amino-3-{3-(2-furfurylideneamido)-2-oxoimidazolidin-1-yl}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

(2) In 13 ml of methylene chloride was dissolved 190 mg ofD-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)phenylacetic acid. To thesolution were added, with ice cooling, a catalytic amount ofN,N-dimethylformamide and 0.05 ml of oxalyl chloride. The mixture wasstirred at room temperature for 30 minutes. The reaction mixture wassubjected to evaporation to dryness under reduced pressure to obtainD-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)phenylacetyl chloride.The compound was dissolved in 3 ml of methylene chloride. The solutionwas dropwise added to the solution prepared in (1) above, at -30° to-20° C. The mixture was stirred for 15 minutes at the same temperatureand further for 20 minutes with ice cooling. The reaction mixture waswashed with water and a saturated aqueous sodium chloride solution inthis order and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue was purifiedby column chromatography (eluant: chloroform/acetone=9/1 to 4/1) toobtain 260 mg (yield: 66.8%) of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-pierazinecarboxamido)-α-phenylacetamido[-3-[3-(2-furfurylideneamino)-2-oxoimidazolidin-1-yl]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1710, 1680

NMR (CDCl₃) δ: 1.25(3H, t, J=7 Hz), 3.28(1H, d, J=13 Hz), 3.30-4.30(10H,m), 4.57(1H, d, J=13 Hz), 5.20-5.80(5H, m), 6.49(1H, dd, J=2 Hz, J=3.5Hz), 6.73(1H, d, J=3.5 Hz), 7.20-7.65(9H, m), 7.97(1H, d, J=9.5 Hz),8.18(2H, d, J=9 Hz), 9.95(1H, d, J=6 Hz).

The compounds shown in Table 6 were obtained in the same manner byeffecting acylation using N,N'-dicyclohexylcarbodiimide as a condensingagent, a mixed anhydride, an acid chloride or the like.

In Table 6, R^(1a), R¹⁴ and R each show a substituent of the followingformula, and n is 1 or 2 as shown in Table 6.

                                      TABLE 6                                     __________________________________________________________________________     ##STR91##                                                                    R.sup.1a         R             R.sup.14                                                                          n IR(KBr) cm.sup.-1 :                      __________________________________________________________________________     ##STR92##                                                                                      ##STR93##    PNB 1 1780, 1720, 1680                          ##STR94##       "             "   " 1780, 1710, 1680                          ##STR95##       "             "   " 1780, 1710, 1670                          ##STR96##                                                                                      ##STR97##    PNB 1 1770, 1710, 1680                          ##STR98##       "             "   " 1775, 1720, 1705, 1680                    ##STR99##       "             "   " 1780, 1720, 1680                          ##STR100##      "             "   " 1780, 1720, 1680                          ##STR101##                                                                                     ##STR102##   PNB 1 1780, 1705, 1680                          ##STR103##      "             "   " 1780, 1730, 1710, 1670                    ##STR104##      "             "   " 1780, 1740, 1720, 1670                    ##STR105##      "             "   " 1780, 1710, 1680                          ##STR106##      "             "   " 1780, 1720, 1700, 1670                    ##STR107##      "             "   " 1780, 1720, 1700, 1660                    ##STR108##      "             "   " 1780, 1730, 1710, 1660                    ##STR109##                                                                                     ##STR110##   PNB 1 1780, 1740˜1700, 1680               ##STR111##      "             "   " 1780, 1720, 1700, 1675                    ##STR112##                                                                                     ##STR113##   "   " 1780, 1720, 1670                          ##STR114##      "             "   " 1780, 1730, 1720, 1670                    ##STR115##      "             "   " 1780, 1720, 1670                          ##STR116##                                                                                     ##STR117##   PNB 1 1780, 1710, 1670                          ##STR118##                                                                                     ##STR119##   "   " 1780, 1720, 1670                          ##STR120##      "             "   " 1780, 1715, 1680                          ##STR121##      "             "   " 1780, 1730, 1705, 1670                    ##STR122##      "             "   " 1780, 1730, 1710, 1680                    ##STR123##                                                                                     ##STR124##   PNB 1 1780, 1710, 1765                                           ##STR125##   "   " 1780, 1710, 1680                          ##STR126##      "             "   " 1780, 1730, 1710, 1675                    ##STR127##                                                                                     ##STR128##   DPM " 1680, 1710, 1680                          ##STR129##      "             PNB " 1780, 1720, 1680                          ##STR130##                                                                                     ##STR131##   PNB 1 1780, 1720, 1680                          ##STR132##                                                                                     ##STR133##   "   " 1780, 1720, 1675                          ##STR134##                                                                                     ##STR135##   "   " 1785, 1720, 1675                          ##STR136##      "             "   " 1790, 1725, 1675, 1625                    ##STR137##      "             "   " 1785, 1720, 1680, 1625                    ##STR138##      "             "   " 1785, 1725, 1680                          ##STR139##                                                                                     ##STR140##   PNB 1 1785, 1725, 1680                          ##STR141##      "             "   " 1780, 1720, 1680                          ##STR142##                                                                                     ##STR143##   "   " 1770, 1740, 1720, 1680                    ##STR144##      "             "   " 1780, 1710, 1670                          ##STR145##                                                                                     ##STR146##   DPM " --                                        ##STR147##                                                                                     ##STR148##   PNB 1 --                                        ##STR149##      "             "   2 1785, 1740, 1710, 1675                    ##STR150##      NCHCH.sub.2 Cl                                                                              "   1 1780, 1710, 1680                         __________________________________________________________________________

EXAMPLE 5

DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]aceticacid and(3R,5R,6R)-6-amino-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanewere subjected to condensation reaction using N-hydroxysuccinimide andN,N'-dicyclohexylcarbodiimide to obtain(3R,5R,6R)-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1785, 1720, 1670

The compounds shown in Table 7 were obtained in the same manner.

In Table 7, R^(1a), R¹⁴ and R each show a substituent of the followingformula.

                                      TABLE 7                                     __________________________________________________________________________     ##STR151##                                                                   R.sup.1a        R          R.sup.14                                                                          IR(KBr) cm.sup.-1 :                            __________________________________________________________________________     ##STR152##                                                                                    ##STR153##                                                                              PNB 1780, 1730, 1680                                ##STR154##                                                                                    ##STR155##                                                                              "   1785, 1725, 1680                                ##STR156##     "          "   1780, 1730,  1680                               ##STR157##     "          "   1780, 1725, 1680                                ##STR158##     "          "   1775, 1725, 1670                                ##STR159##     "          "   1780, 1720, 1680                                ##STR160##                                                                                    ##STR161##                                                                              PNB 1780, 1725, 1675                                ##STR162##     "          "   1780, 1720, 1680                                ##STR163##     "          "   1790, 1720, 1705                                ##STR164##                                                                                    ##STR165##                                                                              DPM 1785, 1720, 1670                                ##STR166##     "          "   1780, 1720, 1675                                ##STR167##     "          PNB 1770, 1725, 1710, 1675                         "               "          DPM 1780,                                                                         1720,                                                                         1680                                            ##STR168##     "          "    --                                            __________________________________________________________________________

EXAMPLE 6

In a mixed solvent consisting of 30 ml of methylene chloride and 15 mlof methanol was dissolved 3.00 g of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 1.89 g of 2,4-dinitrophenylhydrazine and 850mg of p-toluenesulfonic acid monohydrate in this order. The mixture wasstirred at room temperature for 1.5 hours. Then, the insolubles wereremoved by filtration. The filtrate was concentrated under reducedpressure. The residue was mixed with a mixed solvent consisting of 30 mlof methylene chloride and 7 ml of methanol. The insolubles were removedby filtration. The filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (eluant:chloroform/methanol=100/1 to 25/1) to obtain 1.56 g (yield: 60.5%) of(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1720, 1700, 1670

NMR (CDCl₃) δ: 3.30(1H, d, J=13 Hz), 3.48(4H, s), 3.59(2H, s), 4.69(1H,d, J=13 Hz), 5.14(2H, s), 5.47(1H, d, J=4 Hz), 5.66(1H, dd, J=4 Hz, J=8Hz), 6.66(1H, d, J=8 Hz), 7.29(5H, s), 7.49(2H, d, J=9 Hz), 8.23(2H, d,J=9 Hz).

The compounds shown in Table 8 were obtained in the same manner.

In Table 8, R^(1a) and R¹⁴ each show a substituent of the followingformula, and n is 1 or 2 as shown in Table 8.

                  TABLE 8                                                         ______________________________________                                         ##STR169##                                                                                                      IR(KBr)                                    R.sup.1a             R.sup.14                                                                              n     cm.sup.-1 :                                ______________________________________                                         ##STR170##          "       1     1780, 1710, 1680                            ##STR171##          "       "     1780, 1710,  1670                           ##STR172##          "       "     1775, 1720, 1690, 1665                      ##STR173##          PNB     1     1780, 1730, 1700, 1680                      ##STR174##          PNB     1     1775, 1710, 1680                            ##STR175##          "       "     1780, 1720, 1670, 1650                      ##STR176##          DPM     "     1785, 1715, 1680                            ##STR177##          PNB     "     1780, 1730, 1680                            ##STR178##          DPM     1     1785, 1725, 1680                            ##STR179##          "       "     1780, 1720, 1680                            ##STR180##          "       "     1780, 1720, 1680                            ##STR181##          "       "     1780, 1725, 1680, 1660                      ##STR182##          PNB     2     1780, 1740, 1710, 1670                      ##STR183##          "       1     --                                          ##STR184##          PNB     1     --                                          ##STR185##          "       "     1785, 1735, 1680                            ##STR186##          "       "     1785, 1720, 1680                            ##STR187##          "       "     1785, 1720, 1680                            ##STR188##          "       "     1780, 1730, 1675                           PMBO                 DPM     "     1785, 1720                                  ##STR189##          "       "     1785, 1725                                 ______________________________________                                    

EXAMPLE 7

In the same manner as in Example 6, there was obtained(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-6-[DL-α-(p-nitrobenzyloxycarbonyl)-α-phenylacetamido]-7-oxo-4-thia-1azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1740, 1680

EXAMPLE 8

In a mixed solvent consisting of 5 ml of methylene chloride and 5 ml ofmethanol was dissolved 500 mg of(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 100 mg of 5-formyl-1,2,3-thiadiazole and acatalytic amount of p-toluenesulfonic acid monohydrate. The mixture wasstirred overnight at room temperature. The solvent was removed bydistillation under reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/acetone=10/1 to 4/1) to obtain 400 mg(yield: 70.7%) of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-phenylacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-[2-oxo-3-(1,2,3-thiadiazol-5-ylmethylideneamino)imidazolidin-1-yl]-4-thia-1azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1710, 1670

NMR (CDCl₃) δ: 1.25(3H, t, J=7 Hz), 3.32(1H, d, J=13 Hz), 3.20-4.30(10H,m), 4.63(1H, d, J=13 Hz), 5.26(2H, s), 5.20-5.80(3H, m), 7.37(5H, s),7.52(2H, d, J=9 Hz), 7.78(1H, d, J=9 Hz), 7.94(1H, s), 8.16(2H, d, J=9Hz), 8.79(1H, s), 9.95(1H, d, J=6 Hz).

The compounds shown in Table 9 were obtained in the same manner.

In Table 9, R^(1a), R¹⁴ and R each show a substituent of the followingformula, and n is 1 or 2 as shown in Table 9.

                                      TABLE 9                                     __________________________________________________________________________     ##STR190##                                                                   R.sup.1a        R                 R.sup.14                                                                          n IR(KBr) cm.sup.-1 :                   __________________________________________________________________________     ##STR191##                                                                                    ##STR192##       PNB 1 1780, 1710, 1680                                       ##STR193##       "   " 1780, 1710, 1680                      "               NCHAc             "   " 1780, 1715, 1680                      "                                                                                              ##STR194##       "   " 1780, 1720, 1680                      "                                                                                              ##STR195##       "   " 1780, 1720, 1680                      "                                                                                              ##STR196##       "   " 1780, 1720, 1670                       ##STR197##                                                                                    ##STR198##       PNB 1 1785, 1715, 1680                      "               NCHCO.sub.2 PNB   "   " 1780, 1760, 1720, 1680                "                                                                                              ##STR199##       "   " 1785, 1720, 1680                      "                                                                                              ##STR200##       "   " 1785, 1720, 1680                      "                                                                                              ##STR201##       DPM " 1785, 1715, 1680                      "                                                                                              ##STR202##       "   " 1780, 1720, 1680                      "                                                                                              ##STR203##       "   " 1780, 1720, 1680                       ##STR204##                                                                                    ##STR205##       DPM 1 1785, 1720, 1680                      "               NCHCHCH.sub.2     "   " 1780, 1720, 1680                      "               NCHC CH           "   " 1785, 1720, 1680                      "                                                                                              ##STR206##       "   " 1785, 1720, 1685                      "                                                                                              ##STR207##       "   " 1780, 1720, 1680                      "                                                                                              ##STR208##       PNB " 1780, 1710, 1680                      "                                                                                              ##STR209##       "   " 1780, 1715, 1680                       ##STR210##     NCHC CH           PNB 1 1780, 1715, 1680                      "               NCHCH.sub.2 Cl    "   " 1780, 1715, 1680                      "                                                                                              ##STR211##       "   2 1785, 1740, 1710, 1675                 ##STR212##                                                                                    ##STR213##       "   1 1780, 1730, 1680                      "                                                                                              ##STR214##       "   " 1780, 1730, 1710, 1680                "               *NCHCHCHCH.sub.2 SO.sub.3 H                                                                     "   " 1780, 1720, 1670                      "               NCHCO.sub.2 DPM   DPM " 1785, 1740, 1720, 1680                 ##STR215##                                                                                    ##STR216##       PNB 1 1680, 1740, 1715, 1680                 ##STR217##     NCHCHCH.sub.2     DPM " 1780, 1720, 1670                      "               *NCHCHCHCO.sub.2 H                                                                              "   " 1790, 1710, 1650                       ##STR218##     NCHCHCH.sub.2     "   " 1785, 1720, 1680                      "               NCHC CH           "   " 1785, 1725, 1675                       ##STR219##                                                                                    ##STR220##       PMB " 1780, 1720, 1655                       ##STR221##                                                                                    ##STR222##       PNB " 1780, 1720, 1675                       ##STR223##                                                                                    ##STR224##       PNB 1 1780, 1710, 1670                      "                                                                                              ##STR225##       "   " 1780, 1710, 1675                      "                                                                                              ##STR226##       "   " 1790, 1710, 1670                      "               NCHC CH           "   " 1780, 1720, 1680                      "               NCHCH.sub.2 Cl    "   " 1780, 1710, 1675                      "                                                                                              ##STR227##       "   " 1780, 1720, 1705, 1675                 ##STR228##                                                                                    ##STR229##       PNB 1 --                                     ##STR230##     NCHCH.sub.2 Cl    "   " 1770, 1710, 1680                       ##STR231##                                                                                    ##STR232##       "   " 1785, 1730, 1680                       ##STR233##     NCHCHO            DPM " 1785, 1735, 1685                      PMBO            "                 "   " 1785, 1720, 1685                       ##STR234##     NCHCHO            DPM 1 1785, 1735, 1685                       ##STR235##     "                 PNB " 1785, 1740, 1680                       ##STR236##     NCHCO.sub.2 H     DPM " --                                    "                                                                                              ##STR237##       "   " --                                     ##STR238##                                                                                    ##STR239##       PNB " 1780, 1720, 1675                      __________________________________________________________________________     Note:                                                                         *A mixture of cis and trans forms                                        

EXAMPLE 9

In 7 ml of methylene chloride was dissolved 300 mg of(3R,5R,6R)-3-(3-amino2-oxoimidazolidin-1-yl)-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 0.035 ml of methanesulfonyl chloride, 0.042ml of pyridine and a catalytic amount of 4-(N,N-dimethylamino)pyridine.The mixture was stirred at room temperature for 3 days. The reactionmixture was mixed with 5 ml of water and adjusted to pH 1.5 with 1Nhydrochloric acid. The organic layer was separated and mixed with 5 mlof water. The mixture was adjusted to pH 7.5 with a saturated aqueoussodium hydrogencarbonate solution. The organic layer was separated anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue was purified by columnchromatography (eluant: benzene/ethyl acetate=10/1 to 3/2) to obtain 250mg (yield: 76.2%) of (3R,5R,6R)-3-(3-methanesulfonylamino-2-oxoimidazolidin-1-yl)-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1785, 1720, 1670

The compounds shown in Table 10 were obtained in the same manner, usingthe reactants shown in Table 10.

In Table 10, R^(1a), R¹⁴ and R each show a substituent of the followingformula.

                                      TABLE 10                                    __________________________________________________________________________     ##STR240##                                                                                  Product                                                        Reactant       R.sup.1a        R             R.sup.14                                                                         IR(KBr) cm.sup.-1             __________________________________________________________________________                                                    :                             MeNCO                                                                                         ##STR241##                                                                                    ##STR242##   PNB                                                                              1780, 1710, 1670              AC.sub.2 O     "               NHAc          "  1780,                                                                         1710,                                                                         1675                          AcOCHO                                                                                        ##STR243##     NHCHO         PNB                                                                              1780, 1735, 1680               ##STR244##    "                                                                                              ##STR245##   "  1780, 1725, 1680               ##STR246##    "                                                                                              ##STR247##   "  1780, 1740, 1715, 1680        Ac.sub.2 O     "               NHAc          "  1785,                                                                         1730,                                                                         1680                           ##STR248##                                                                                   ##STR249##                                                                                    ##STR250##   PNB                                                                              1770, 1730, 1665              NH.sub.2 COCOOH*.sup.3                                                                       "                                                                                              ##STR251##   "  1780, 1735, 1680              NH.sub.2 OBzl*.sup.4                                                                         "                                                                                              ##STR252##   "  1780, 1735, 1680              Ac.sub.2 O                                                                                    ##STR253##     NHAc          "  1780, 1720, 1680              (CF.sub.3 CO).sub.2 O                                                                        "                                                                                              ##STR254##   "  1785, 1745, 1725, 1675        (EtCO).sub.2 O                                                                                ##STR255##                                                                                    ##STR256##   PNB                                                                              1790, 1730, 1680              MeNCO          "                                                                                              ##STR257##   "  1780, 1720, 1680               ##STR258##    "                                                                                              ##STR259##   "  1780, 1730, 1705, 1680         ##STR260##    "                                                                                              ##STR261##   "  1780, 1730, 1675               ##STR262##    "                                                                                              ##STR263##   "  1785, 1725, 1700               ##STR264##                                                                                   ##STR265##                                                                                    ##STR266##   PNB                                                                              1785, 1715, 1675              ClCOCHCH.sub.2                                                                                ##STR267##     NHCOCHCH.sub.2                                                                              DPM                                                                              1790, 1730, 1680              ClSO.sub.2 NH.sub.2                                                                          "               NHSO.sub.2 NH.sub.2                                                                         "  1780,                                                                         1710                           ##STR268##    "                                                                                              ##STR269##   "  1790, 1730, 1680              ClCOCH.sub.2 NHCO.sub.2 PNB                                                                  "               NHCOCH.sub.2 NHCO.sub.2 PNB                                                                 "  --                            __________________________________________________________________________     Note                                                                          *.sup.1 Acylation was effected using N,N'-dicyclohexylcarbodiimide and        Nhydroxysuccinimide.                                                          *.sup.2 Only pyridine was used as the base.                                   *.sup.3 Acylation was effected using N,N'-dicyclohexylcarbodiimide.           *.sup.4 Acylation was effected using 1,1'-carbonyldiimidazole.           

EXAMPLE 10

In 5 ml of N,N-dimethylformamide was dissolved 390 mg of(3R,5R,6R)-3-[3-(2-chloroethylideneamino)-2-oxoimidazolidin-1-yl]-6-[D-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 70 mg of sodium salt of5-mercapto-1,2,3-thiadiazole and a catalytic amount of sodium iodide inthis order. The mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (eluant: chloroform/acetone=5/1 to1/1) to obtain 190 mg (yield: 44.8%) of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-3-{3-[2-(1,2,3-thiadiazol-5-ylthio)ethylideneamino]-2-oxoimidazolidin-1-yl}-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1710, 1670

The compounds shown in Table 11 were obtained in the same manner.

In Table 11, R^(1a) and R each show a substituent of the followingformula.

                                      TABLE 11                                    __________________________________________________________________________     ##STR270##                                                                   R.sup.1a        R              IR(KBr) cm.sup.-1 :                            __________________________________________________________________________     ##STR271##                                                                                    ##STR272##    1780, 1710, 1675                                ##STR273##     "              1780, 1715, 1670                                                ##STR274##    1780, 1710, 1670                               __________________________________________________________________________

EXAMPLE 11

In a mixed solvent consisting of 5 ml of methylene chloride and 5 ml ofmethanol was dissolved 400 mg of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-phenylacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-propynylideneaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 110 mg of sodium salt of5-mercapto-1,2,3-thiadiazole and 198 mg of pyridine salt ofp-toluenesulfonic acid. The mixture was stirred at room temperature for2 days. To the reaction mixture were added 10 ml of water and 10 ml ofmethylene chloride. The mixture was adjusted to pH 7.0 with a saturatedaqueous sodium hydrogencarbonate solution. The organic layer wasseparated and mixed with 10 ml of water. The mixture was adjusted to pH2.0 with 2N hydrochloric acid. The organic layer was separated andtreated with active carbon. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/acetone=20/1 to 3/2) to obtain 290 mg(yield: 63.6%) of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-phenylacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-{2-oxo-3-[3-(1,2,3-thiadiazol-5-ylthio)allylideneamino]imidazolidin-1-yl}-4-thia-1-azabicyclo[3.2.0]heptane(a mixture of cis and trans forms).

IR (KBr) cm⁻¹ : 1780, 1710, 1675

The compounds shown in Table 12 were obtained in the same manner.

In Table 12, R^(1a) and R each show a substituent of the followingformula.

                                      TABLE 12                                    __________________________________________________________________________     ##STR275##                                                                   R.sup.1a       R                   IR(KBr) cm.sup.-1 :                        __________________________________________________________________________     ##STR276##                                                                                   ##STR277##         1780, 1710, 1680                                           ##STR278##         1780, 1710, 1680                            ##STR279##                                                                                   ##STR280##         1780, 1710, 1670                           __________________________________________________________________________     Note:                                                                         *A mixture of cis and trans forms                                        

EXAMPLE 12

To a mixed solvent consisting of 5 ml of ethylacetate and 5 ml of waterwere added 200 mg of 5% palladium-carbon and 220 mg of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-phenylacetamido]-3-[3-(2-furfurylideneamino)-2-oxoimidazolidin-1-yl]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.The mixture was stirred at room temperature for 2 hours in a hydrogenatmosphere. The insolubles were removed by filtration. The filtrate wasadjusted to pH 6.5 with a saturated aqueous sodium hydrogencarbonatesolution. The aqueous layer was separated and freeze-dried to obtain 50mg (yield: 26.5%) of sodium salt of(3R,5R,6R)-3-carboxy-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetamido]-3-[3-(2-furfurylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1670, 1620

NMR (D₂ O) δ: 1.17(3H, t, J=7 Hz), 3.20-4.20(1H, m), 5.40(1H, d, J=4Hz), 5.48(1H, s), 5.54(1H, d, J=4 Hz), 6.58(1H, dd, J=2 Hz, J=3 Hz),6.80(1H, d, J=3 Hz), 7.48(5H, s), 7.40-7.70(2H, m)

The compounds shown in Table 13 were obtained in the same manner.

In Table 13, R^(1a), R¹⁵ and R^(a) each show a substituent of thefollowing formula, and n is 1 or 2 as shown in Table 13.

                                      TABLE 13                                    __________________________________________________________________________     ##STR281##                                                                   R.sup.1a         R.sup.a             R.sup.15                                                                         n IR(KBr) cm.sup.-1 :                 __________________________________________________________________________     ##STR282##                                                                                     ##STR283##         Na 1 1770, 1705, 1670, 1620               ##STR284##      "                   H  " 1780, 1710, 1670, 1650               ##STR285##      "                   "  " 1770, 1700, 1660                     ##STR286##                                                                                     ##STR287##         H  1 1770, 1710, 1670, 1650               ##STR288##      "                   "  " 1775, 1705, 1680, 1650               ##STR289##      "                   "  " 1765, 1680, 1610                     ##STR290##      "                   "  " 1780, 1705, 1690                     ##STR291##      "                   "  " 1765, 1680, 1605                     ##STR292##                                                                                     ##STR293##         H  1 1780, 1705,  1670                    ##STR294##      "                   "  " 1770, 1720, 1700, 1650               ##STR295##      "                   Na " 1770, 1700, 1610                     ##STR296##      "                   H  " 1780, 1720, 1680, 1650               ##STR297##      "                   Na " 1770, 1700˜ 1660, 1620         ##STR298##      "                   "  " 1770, 1690, 1650, 1615               ##STR299##      "                   H  " 1770, 1700˜ 1660, 1610         ##STR300##                                                                                     ##STR301##         H  1 1770, 1700, 1680, 1605               ##STR302##                                                                                     ##STR303##         "  " 1775, 1700, 1660, 1620               ##STR304##      "                   "  " 1775, 1720, 1680                     ##STR305##      "                   "  " 1780, 1710, 1680                    "                "                   Na 2 1770,                                                                         1710,                                                                         1670,                                                                         1615                                 ##STR306##                                                                                     ##STR307##         H  1 1780, 1715, 1650                     ##STR308##                                                                                     ##STR309##         H  1 1770, 1685, 1610                     ##STR310##      "                   Na " 1775, 1710, 1675, 1620               ##STR311##      "                   "  " 1770, 1710, 1675, 1620               ##STR312##                                                                                     ##STR313##         "  " 1770, 1710, 1660, 1610                                ##STR314##         H  " 1780, 1710, 1675                     ##STR315##      "                   "  " 1775, 1715, 1670                     ##STR316##                                                                                     ##STR317##         Na 1 1760, 1710, 1660, 1610               ##STR318##                                                                                     ##STR319##         "  " 1770, 1730, 1670, 1600               ##STR320##      "                   "  " 1760, 1710, 1660, 1600               ##STR321##      "                   "  " 1765, 1705, 1660, 1600               ##STR322##                                                                                     ##STR323##         "  " 1770, 1710, 1690, 1675, 1600         ##STR324##                                                                                     ##STR325##         Na 1 1770, 1700, 1670, 1620              "                                                                                               ##STR326##         "  " 1770, 1705, 1670, 1610              "                NCHAc               "  " 1780,                                                                         1720,                                                                         1670,                                                                         1615                                "                                                                                               ##STR327##         H  " 1780, 1715, 1675                    "                                                                                               ##STR328##         "  " 1780, 1715, 1680                    "                                                                                               ##STR329##         Na " 1770, 1705, 1670, 1615              "                                                                                               ##STR330##         "  " 1775, 1715, 1675, 1605               ##STR331##      NCHCO.sub.2 Na      Na 1 1770, 1710, 1670, 1600              "                                                                                               ##STR332##         "  " 1770, 1710, 1670, 1600              "                                                                                               ##STR333##         "  " 1775, 1710, 1680, 1610              "                                                                                               ##STR334##         H  " 1780, 1710, 1665                    "                NHHAc               "  " 1780,                                                                         1710,                                                                         1670                                "                                                                                               ##STR335##         Na " 1775, 1710, 1675, 1615              "                                                                                               ##STR336##         "  " 1775, 1710, 1670, 1620               ##STR337##                                                                                     ##STR338##         Na 1 1770, 1710, 1675, 1615              "                                                                                               ##STR339##         "  " 1780, 1720, 1680, 1620              "                                                                                               ##STR340##         H  " 1775, 1710, 1680, 1610              "                                                                                               ##STR341##         Na " 1775, 1710, 1675, 1620               ##STR342##                                                                                     ##STR343##         "  " 1775, 1710, 1670, 1610               ##STR344##                                                                                     ##STR345##         "  " 1770, 1710, 1670, 1610               ##STR346##                                                                                     ##STR347##         Na 1 1775, 1710, 1670, 1610              "                                                                                               ##STR348##         "  " 1770, 1710, 1670, 1610              "                                                                                               ##STR349##         "  " 1765, 1705, 1670, 1600              "                                                                                               ##STR350##         "  " 1780, 1710, 1680, 1610              "                                                                                               ##STR351##         "  " 1770, 1710, 1670, 1605              "                                                                                               ##STR352##         "  " 1770, 1710, 1670, 1615              "                                                                                               ##STR353##         "  " 1775, 1710, 1670, 1610               ##STR354##                                                                                     ##STR355##         Na 1 1765, 1705, 1670, 1620              "                NH.sub.2            "  " 1770,                                                                         1710,                                                                         1670,                                                                         1600                                 ##STR356##                                                                                     ##STR357##         H  " 1775, 1710, 1660, 1620               ##STR358##                                                                                     ##STR359##         "  " 1770, 1720, 1700                     ##STR360##      NH.sub.2            Na " 1770, 1695, 1660, 1610               ##STR361##      ∝1           "  " 1770, 1710, 1660,  1600              ##STR362##                                                                                     ##STR363##         H  " 1775, 1730, 1705, 1660               ##STR364##                                                                                     ##STR365##         Na 1 1770, 1710, 1660, 1610              "                                                                                               ##STR366##         "  " 1770, 1720, 1675, 1600              "                NHAc                "  " 1760,                                                                         1710,                                                                         1620,                                                                         1605                                "                NHCHO               "  " 1770,                                                                         1710,                                                                         1660,                                                                         1600                                "                                                                                               ##STR367##         "  " 1770, 1670, 1600                    "                                                                                               ##STR368##         "  " 1770, 1710, 1660, 1600              "                                                                                               ##STR369##         "  " 1765, 1700, 1660, 1600               ##STR370##      NHSO.sub.3 Na       Na 1 1760, 1700, 1660, 1600               ##STR371##                                                                                     ##STR372##         "  " 1770, 1710, 1670, 1610              __________________________________________________________________________

The compounds wherein R¹⁵ was a hydrogen atom, were obtained by, afterthe hydrogenation, removing the insolubles by filtration, adding to thefiltrate a mixed solvent of ethyl acetate and tetrahydrofuran, adjustingthe resulting mixture to pH 2.0 with 1N hydrochloric acid, separatingthe organic layer, and subjecting the organic layer to washing withwater, drying over anhydrous magnesium sulfate and distillation forsolvent removal.

EXAMPLE 13

The compounds shown in Table 14 were obtained in the same manner as inExample 12

In Table 14, R^(a) and R^(1a) each show a substituent of the followingformula.

                                      TABLE 14                                    __________________________________________________________________________     ##STR373##                                                                   R.sup.1a       R.sup.a        IR(KBr) cm.sup.-1 :                             __________________________________________________________________________     ##STR374##                                                                                   ##STR375##    1770, 1700, 1600                                 ##STR376##    NCHCHNOMe      1770, 1610                                       ##STR377##    NHCONH.sub.2   1750, 1660-1600                                  ##STR378##    "              1765, 1710, 1700, 1680-1660, 1600                ##STR379##                                                                                   ##STR380##    1765, 1700, 1650, 1610                          __________________________________________________________________________

EXAMPLE 14

In the same manner as in Example 12, there was obtained disodium salt of(3R,5R,6R)-3-carboxy-6-[DL-α-carboxy-α-phenylacetamido]-6-methoxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1670, 1600

EXAMPLE 15

(1) In a mixed solvent consisting of 1 ml of methylene chloride and 1 mlof anisole was dissolved 210 mg of(3R,5R,6R)-3-diphenylmethyloxycarbonyl-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetamido]-3-[3-(4-nitrobenzylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -30° C.

(2) 95 mg of anhydrous aluminum chloride was dissolved in 1 ml ofanisole. This solution was added to the solution prepared in (1) above,at -30° C. The mixture was stirred at -20° C. for 20 minutes. Thereaction mixture was added to a mixed solvent consisting of 10 ml oftetrahydrofuran, 20 ml of ethyl acetate and 10 ml of water. Theresulting mixture was adjusted to pH 1.0 with 1N hydrochloric acid. Theinsolubles were removed by filtration. The organic layer was separatedand mixed with 10 ml of water. The mixture was adjusted to pH 6.5 with asaturated aqueous sodium hydrogencarbonate solution. The aqueous layerwas separated and freeze-dried to obtain 120 mg (yield: 72.5%) of sodiumsalt of(3R,5R,6R)-3-carboxy-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetamido]-3-[3-(4-nitrobenzylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1675, 1615

The compounds shown in Table 15 were obtained in the same manner.

In Table 15, R^(1a), R¹⁵ and R each show a substituent of the followingformula.

                                      TABLE 15                                    __________________________________________________________________________     ##STR381##                                                                   R.sup.1a        R                    R.sup.15                                                                         IR (KBr) cm.sup.-1 :                  __________________________________________________________________________     ##STR382##                                                                                    ##STR383##          Na 1780, 1710, 1680, 1620                                 ##STR384##          "  1780, 1720, 1675, 1610                "                                                                                              ##STR385##          "  1780, 1710, 1680, 1620                "               NCHCHCH.sub.2        "  1770, 1705, 1675, 1605                "               NCHCCH               "  1770, 1710, 1670, 1620                "                                                                                              ##STR386##          H  1780, 1710, 1670                       ##STR387##     NCHCHCH.sub.2        Na 1770, 1700, 1650, 1600                "               NCHCCH               "  1770, 1705, 1655, 1600                 ##STR388##     * NCHCHCHCO.sub.2 Na "  1770, 1690, 1660, 1610                "               NCHCHCH.sub.2        "  1770, 1700, 1650, 1600                "               NCHCHNOCH.sub.2 CO.sub.2 Na                                                                        "  1770, 1705, 1600                       ##STR389##     NCHCHNNHCONH.sub.2   "  1760, 1660, 1600                      "               NCHCHNNHCHO          "  1765, 1680, 1600                       ##STR390##                                                                                    ##STR391##          Na 1770, 1690, 1620                      "                                                                                              ##STR392##          "  1760, 1600                            "               NHCONHSO.sub.2 NH.sub.2                                                                            "  1760, 1600                             ##STR393##     NCHCHCHCN            "  1765, 1705, 1600                      "               NCHCONH.sub.2        "  1770, 1720, 1660, 1600                "               NCHCHCHCONH.sub.2    "  1765, 1700, 1660, 1600                "               NCHCN                "  1770, 1720, 1660, 1610                "                                                                                              ##STR394##          "  1770, 1710, 1690, 1660, 1610           ##STR395##                                                                                    ##STR396##          Na 1770, 1710, 1680˜1660,                                                  1600                                  "               NHCOCHCH.sub.2       "  1770, 1710, 1680˜1650,                                                  1600                                  "               NHSO.sub.2 NH.sub.2  "  1760, 1700, 1650, 1620, 1600          "                                                                                              ##STR397##          "  1770, 1700, 1600                      __________________________________________________________________________     Note:                                                                         *A mixture of cis and trans forms                                        

EXAMPLE 16

(1) In 6 ml of methylene chloride was dissolved 300 mg of(3R,5R,6R)-3-(3-acetylamino-2-oxoimidazolidin-1-yl)-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -30° C. To the solution was dropwise added 2ml of an anisole solution containing 280 mg of anhydrous aluminumchloride, while maintaining the reaction temperature at -20° C. orbelow. The mixture was stirred at -10° to 0° C. for 30 minutes. Thereaction mixture was added to a mixed solvent consisting of 10 ml ofwater, 15 ml of ethyl acetate and 10 ml of tetrahydrofuran. Theresulting mixture was adjusted to pH 1.0 with 2N hydrochloric acid. Theorganic layer was separated and mixed with 10 ml of water. The mixturewas adjusted to pH 7.5 with a saturated aqueous sodium hydrogencarbonatesolution. The aqueous layer was separated. Thereto were added 15 ml ofethyl acetate and 10 ml of tetrahydrofuran. The mixture was adjusted topH 1.0 with 2N hydrochloric acid. The organic layer was separated,washed with a saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure to obtain 160 mg of(3R,5R,6R)-3-(3-acetylamino-2-oxoimidazolidin-1-yl)-6-[DL-α-carboxy-α-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

(2) In a mixed solvent consisting of 3 ml of water, 3 ml of methanol and3 ml of tetrahydrofuran was dissolved 160 mg of(3R,5R,6R)-3-(3-acetylamino-2-oxoimidazolidin-1-yl)-6-[DL-α-carboxy-α-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution was added 150 mg of 5% palladium-carbon. The mixture wasstirred at room temperature for 2 hours in a hydrogen atmosphere. Theinsolubles were removed by filtration. The filtrate was concentratedunder reduced pressure. To the residue were added 5 ml of water and 10ml of ethyl acetate. The mixture was adjusted to pH 6.5 with a saturatedaqueous sodium hydrogencarbonate solution. The aqueous layer wasseparated, purified by reversed phase column chromatography (eluant:water) and freeze-dried to obtain 120 mg (yield: 64.2%) of disodium saltof(3R,5R,6R)-3-(3-acetylamino-2-oxoimiaazolidin-1-yl)-3-carboxy-6-[DL-.alpha.-carboxy-α-(p-hydroxyphenyl)acetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1650, 1600,

The compounds shown in Table 16 were obtained in the same manner.

In Table 16, R^(1a) and R each show a substituent of the followingformula.

                                      TABLE 16                                    __________________________________________________________________________     ##STR398##                                                                   R.sup.1a          R             IR (KBr) cm.sup.-1 :                          __________________________________________________________________________     ##STR399##                                                                                      ##STR400##   1770, 1710, 1660, 1600                                           ##STR401##   1765, 1690, 1655, 1605                        "                                                                                                ##STR402##   1770, 1710, 1660, 1600                        "                 NHSO.sub. 2 Me                                                                              1760, 1700, 1650, 1600                        "                                                                                                ##STR403##   1760, 1720, 1660, 1600                        "                                                                                                ##STR404##   1770, 1710, 1660, 1625, 1600                   ##STR405##                                                                                      ##STR406##   1770, 1710, 1660, 1610                        "                 NH.sub.2      1760, 1690, 1650, 1610                        "                                                                                                ##STR407##   1770, 1700, 1660, 1600                         ##STR408##       "             1770, 1710, 1660, 1600                        "                 NH.sub.2      1760, 1705, 1660, 1600                         ##STR409##       "             1770, 1710, 1660, 1610                         ##STR410##       "             1760, 1710, 1650, 1600                         ##STR411##       NH.sub.2      1770, 1710, 1660, 1605                         ##STR412##                                                                                      ##STR413##   1765, 1705, 1670, 1600                         ##STR414##       "             1770, 1715, 1670, 1600                         ##STR415##       "             1765, 1710, 1665, 1600                         ##STR416##       NCHCO.sub.2 Na                                                                              1765, 1700, 1650, 1600                         ##STR417##                                                                                      ##STR418##   1770, 1660, 1600                               ##STR419##                                                                                      ##STR420##   1770, 1700˜1660, 1600                   __________________________________________________________________________

EXAMPLE 17

(1)(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanein place of(3R,5R,6R)-3-(3-acetylamino-2-oxoimidazolidin-1-yl)-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanewas subjected to the same procedure as in Example 16 (1) to obtain(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-6-[DL-α-carboxy-.alpha.-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1720, 1670

(2) In 3 ml of N,N-dimethylformamide was dissolved 250 mg of(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-6-[DL-α-carboxy-.alpha.-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution was added 130 mg of a sulfur trioxide-pyridine complex,and the mixture was stirred at room temperature for 1 day. The reactionmixture was poured into 10 ml of water in 5 minutes while maintainingthe reaction mixture at pH 6.0 to 7.0 with a saturated aqueous sodiumhydrogencarbonate solution. The reaction mixture was concentrated underreduced pressure. The residue was dissolved in a mixed solventconsisting of 10 ml of water and 10 ml of ethyl acetate. The solutionwas adjusted to pH 2.0 with 1N hydrochloric acid. The aqueous layer wasseparated, adjusted to pH 6.0 with a saturated aqueous sodiumhydrogencarbonate solution, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (eluant:water) to obtain 30 mg (yield: 9.9%) of disodium salt of(3R,5R,6R)-6-[DL-α-carboxy-α-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-sulfoaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1740, 1710, 1655, 1600

EXAMPLE 18

To a mixed solvent consisting of 2 ml of tetrahydrofuran, 2 ml ofmethanol and 2 ml of water were added 200 mg of an iron powder, 200 mgof ammonium chloride and 100 mg of(3R,5R,6R)-3-(p-nitrobenzyloxycarbonyl)-6-[DL-α-(p-nitrobezyloxycarbonyl)-α-phenylacetamido]-7-oxo-3-[2-oxo-3-(4-sulfo-2-butenylideneamino)imidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptane.The mixture was stirred at room temperature for 6 hours. The insolubleswere removed by filtration. The filtrate was concentrated under reducedpressure. To the residue were added 5 ml of ethyl acetate and 5 ml ofwater. The mixture was adjusted to pH 6.0 with a saturated aqueoussodium hydrogencarbonate solution. The aqueous layer was separated andpurified by reversed phase column chromatography (eluant: water) toobtain 30 mg (yield: 39.5%) of trisodium salt of(3R,5R,6R)-3-carboxy-6-(DL-α-carboxy-α-phenylacetamido)-7-oxo-3-[3-(4-sulfo-2-butenylideneamino)-2-oxoimidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1660, 1600

EXAMPLE 19

In 5 ml of N,N-dimethylformamide was dissolved 300 mg of(3R,5R,6R)-3-[3-(2-chloroethylideneamino)-2-oxoimidazolidin-1-yl]-6-[D-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(p-hydroxyphenyl)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 3 ml of pyridine and a catalytic amount ofsodium iodide. The mixture was stirred at room temperature for 1 day.The reaction mixture was subjected to evaporation to dryness underreduced pressure. The residue was dissolved in a mixed solventconsisting of 5 ml of water, 5 ml of methanol and 5 ml of ethyl acetate.To the solution was added 300 mg of 5% palladium-carbon. The mixture wasstirred at room temperature for 5 hours in a hydrogen atmosphere. Theinsolubles were removed by filtration. The filtrate was concentratedunder reduced pressure. To the residue were added 20 ml of water and 20ml of ethyl acetate. The mixture was adjusted to pH 7.0 with a saturatedsodium hydrogencarbonate solution. The aqueous layer was separated,purified by reversed phase column chromatography (eluant:water/acetonitrile=9/1 to 6/1), and freeze-dried to obtain 67 mg (yield:25.3%) of(3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-(p-hydroxyphenyl)acetamido]-7-oxo-3-{2-oxo-3-[2-(1-pyridinium)ethylideneamino]imidazolidin-1-yl}-4-thia-1-azabicyclo[3.2.0]heptane-3-carboxylate.

IR (KBr) cm⁻¹ : 1770, 1710, 1665, 1615

The compounds shown in Table 17 were obtained in the same manner.

In Table 17, R^(1a) and R each show a substituent of the followingformula.

                                      TABLE 17                                    __________________________________________________________________________     ##STR421##                                                                   R.sup.1a       R                     IR(KBr) cm.sup.-1 :                      __________________________________________________________________________     ##STR422##                                                                                   ##STR423##           1775, 1715, 1670, 1620                                   ##STR424##           1770, 1705 1670, 1630, 1610              "                                                                                             ##STR425##           1770, 1705, 1665, 1610                   "                                                                                             ##STR426##           1770, 1700, 1670, 1605                   "                                                                                             ##STR427##           1775, 1710, 1670, 1615                    ##STR428##                                                                                   ##STR429##           1775, 1710, 1670, 1620                   "                                                                                             ##STR430##           1770, 1710, 1670, 1620                   "                                                                                             ##STR431##           1770, 1710, 1670, 1620                   "                                                                                             ##STR432##           1770, 1710, 1670, 1615                   "                                                                                             ##STR433##           1780, 1710, 1675, 1620                   "                                                                                             ##STR434##           1770, 1705, 1670, 1605                   "                                                                                             ##STR435##           1770, 1720, 1670, 1620, 1600              ##STR436##                                                                                   ##STR437##           1770, 1710, 1670, 1620                   "                                                                                             ##STR438##           1770, 1750, 1665, 1610                   "                                                                                             ##STR439##           1775, 1710, 1670, 1650, 1610             "                                                                                             ##STR440##           1770, 1710, 1670, 1610                   "                                                                                             ##STR441##           1770, 1710, 1670, 1615                   "                                                                                             ##STR442##           1770, 1710, 1670, 1610                    ##STR443##                                                                                   ##STR444##           1780, 1720, 1680, 1620                   "                                                                                             ##STR445##           1770, 1710, 1670, 1610                    ##STR446##    "                     1775, 1710, 1670, 1620                    ##STR447##                                                                                   ##STR448##           1770, 1710, 1670, 1620                   __________________________________________________________________________

EXAMPLE 20

(1) 250 mg of p-acetoxyphenylacetic acid was dissolved in 5 ml ofmethylene chloride. To the solution were added, with ice cooling, acatalytic amount of N,N-dimethylformamide and 0.12 ml of oxalylchloride. The mixture was stirred at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure to obtainp-acetoxyphenylacetyl chloride. This compound was dissolved in 5 ml ofmethylene chloride. To the solution was added 260 mg of a sulfurtrioxide-dioxane complex with ice cooling. The mixture was stirred atroom temperature for 2 hours. The solvent was removed by distillationunder reduced pressure to obtain DL-2-(p-acetoxyphenyl)-2-sulfoacetylchloride. This compound was dissolved in 5 ml of anhydroustetrahydrofuran.

(2) In a mixed solvent consisting of 5 ml of tetrahydrofuran and 5 ml ofwater was dissolved 300 mg of(3R,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.To this solution was dropwise added the tetrahydrofuran solution ofDL-2-(p-acetoxyphenyl)-2-sulfoacetyl chloride prepared in (1) above,with ice-cooling while maintaining the pH at 7.0 to 7.5 with a saturatedaqueous sodium hydrogencarbonate solution. After the dropwise addition,the mixture was stirred at the same temperature for 10 minutes. To themixture was added 5 ml of ethyl acetate, and adjusted to pH 6.0 with 1Nhydrochloric acid. The aqueous layer was separated. Water was removed bydistillation under reduced pressure. The residue was purified byreversed phase column chromatography (eluent: water/acetonitrile=1/0 to9/1) to obtain 340 mg (yield: 70.8%) of sodium salt of(3R,5R,6R)-6-[DL-α-(p-acetoxyphenyl)-α-sulfoacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1775, 1720, 1670

The compounds shown in Table 18 were obtained in the same manner.

In Table 18, R^(1a) and R each show a substituent of the followingformula.

                                      TABLE 18                                    __________________________________________________________________________     ##STR449##                                                                   R.sup.1a        R           IR (KBr) cm.sup.-1 :                              __________________________________________________________________________     ##STR450##                                                                                    ##STR451## 1770, 1710, 1660, 1620                                             ##STR452##   --                                              "                                                                                              ##STR453##   --                                               ##STR454##     "             --                                              "                                                                                              ##STR455## 1770, 1715, 1670                                   ##STR456##     "           1770, 1710, 1670, 1620                             ##STR457##                                                                                    ##STR458##   --                                               ##STR459##     "           1770, 1725, 1670                                   ##STR460##     "           1770, 1720, 1670                                   ##STR461##     "           1775, 1730, 1675                                   ##STR462##     "           1780, 1725, 1685                                   ##STR463##     "           1780, 1720, 1680                                   ##STR464##                                                                                    ##STR465## 1770, 1720, 1670                                   ##STR466##     "           1770, 1720, 1680                                   ##STR467##     "           1775, 1725, 1670                                   ##STR468##     "           1770, 1705, 1660, 1600                             ##STR469##     "           1780, 1720, 1670                                   ##STR470##     "           1760, 1720, 1705, 1675                            __________________________________________________________________________

EXAMPLE 21

(3R,5R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanewas reacted with DL-α-(p-nitrobenzyloxycarbonyl)-α-phenylacetic acid inplace of(3R,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptanein the same manner as in Example 20 to obtain(3R,5R,6R)-3-(3-benzylideneamino-6-[DL-α-(p-nitrobenzyloxycarbonyl)-α-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1740, 1710, 1690

EXAMPLE 22

10 ml of water was added to 150 mg of 5% palladium-carbon and 330 mg ofsodium salt of(3R,5R,6R)-6-[DL-α-(p-acetoxyphenyl)-α-sulfoacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.The mixture was stirred at room temperature for 2 hours in a hydrogenatmosphere. The insolubles were removed by filtration. 10 ml of ethylacetate was added to the filtrate, and the mixture was adjusted to pH6.0 with a saturated aqueous sodium hydrogencarbonate solution. Theaqueous layer was separated. Water was removed by distillation underreduced pressure. The residue was purified by reversed phase columnchromatography (eluant: water) and freeze-dried to obtain 210 mg (yield:47.1%) of disodium salt of(3R,5R,6R)-6-[DL-α-(p-acetoxyphenyl)-α-sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1760, 1710, 1670, 1610

The compounds shown in Table 19 were obtained in the same manner.

In Table 19, R^(1a) and R each show a substituent of the followingformula.

                  TABLE 19                                                        ______________________________________                                         ##STR471##                                                                                                   IR(KBr)                                       R.sup.1a        R               cm.sup.-1 :                                   ______________________________________                                         ##STR472##                                                                                    ##STR473##     1770, 1710, 1660, 1620                                         ##STR474##     1770, 1660, 1620                              "                                                                                              ##STR475##     1770, 1670, 1620                               ##STR476##     "               1760, 1660, 1620                              "                                                                                              ##STR477##     1760, 1705, 1670, 1615                         ##STR478##     "               1770, 1710, 1670, 1620                         ##STR479##                                                                                    ##STR480##     1770, 1710, 1670, 1620                         ##STR481##     "               1765, 1705, 1670, 1620                         ##STR482##     "               1760, 1665, 1615                               ##STR483##     "               1760, 1700, 1670, 1615                         ##STR484##     "               1765, 1710, 1670, 1620                         ##STR485##     "               1775, 1710, 1675, 1620                         ##STR486##                                                                                    ##STR487##     1760, 1700, 1670, 1610                         ##STR488##     "               1760, 1710, 1670, 1620                         ##STR489##     "               1765, 1705, 1665, 1615                         ##STR490##     "               1770, 1710, 1670, 1610                         ##STR491##     "               1770, 1720, 1700, 1670, 1610                   ##STR492##     "               1770, 1710, 1675, 1620                        ______________________________________                                    

EXAMPLE 23

In 5 ml of water was dissolved 200 mg of disodium salt of(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-carboxy-6-(DL-α-carboxy-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.To the solution were added 0.5 ml of 1N hydrochloric acid and 31 mg ofsodium cyanate. The mixture was stirred at room temperature for 30minutes and adjusted to pH 6.5 with a saturated aqueous sodiumhydrogencarbonate solution. The reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (eluant: water) and freeze-dried to obtain 160 mg (yield:73.7%) of disodium salt of(3R,5R,6R)-3-carboxy-6-(DL-α-carboxy-α-phenylacetamido)-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1760, 1705, 1660, 1600

NMR (D₂ O) δ: 3.60 (4H, s), 5.48-5.64 (2H, m), 7.40 (5H, s)

The compounds shown in Table 20 were obtained in the same manner.

In Table 20, R^(1a) shows a substituent of the following formula.

                  TABLE 20                                                        ______________________________________                                         ##STR493##                                                                   R.sup.1a               IR(KBr)cm.sup.-1 :                                     ______________________________________                                         ##STR494##            1770, 1710, 1670, 1605                                  ##STR495##            1770, 1700, 1660, 1580                                  ##STR496##            1765, 1700, 1660, 1590                                  ##STR497##            1770, 1730, 1670, 1600                                  ##STR498##            1760, 1710, 1660, 1600                                  ##STR499##            1765, 1710, 1660, 1600                                  ##STR500##            1770, 1710, 1665, 1600                                 ______________________________________                                    

EXAMPLE 24

The compounds shown in Table 21 were obtained in the same manner as inExample 23.

In Table 21, R and R^(1a) each show a substituent of the followingformula.

                                      TABLE 21                                    __________________________________________________________________________     ##STR501##                                                                   R.sup.1a       R            IR(KBr) cm.sup.-1 :                               __________________________________________________________________________     ##STR502##    NHCONH.sub.2 --                                                 ##STR503##    "            1765, 1700-1660, 1620                              ##STR504##    NHCOCH.sub.2 NHCONH.sub.2                                                                  1770, 1730-1660, 1600                             __________________________________________________________________________

EXAMPLE 25

In 2 ml of N,N-dimethylformamide were dissolved 53 mg of1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, 40 mg ofN-hydroxysuccinimide and 71 mg of N,N'-dicyclohexylcarbodiimide. Thesolution was stirred at room temperature for 2 hours. To the reactionmixture were added 150 mg of(3R,5R,6R)-6-(D-α-amino-α-phenylacetamido)-3-carboxy-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneand 0.06 ml of triethylamine in this order. The mixture was stirred atroom temperature for 2 hours. The insolubles were removed by filtration.The solvent was removed by distillation under reduced pressure. To theresidue were added 15 ml of ethyl acetate and 10 ml of water. Themixture was adjusted to pH 7.0 with a saturated aqueous sodiumhydrogencarbonate solution. The aqueous layer was separated. Water wasremoved by distillation under reduced pressure. The residue was purifiedby reversed phase column chromatography (eluant: water/acetonitrile=1/0to 9/1) and freeze-dried to obtain 35 mg (yield: 17.9%) of sodium saltof(3R,5R,6R)-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-3-carboxy-6-{D-α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)carboxamido]-α-phenylacetamido}-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1660, 1610

The compounds shown in Table 22 were obtained in the same manner.

In Table 22, R^(1a) shows a substituent of the following formula.

                  TABLE 22                                                        ______________________________________                                         ##STR505##                                                                   R.sup.1a               IR(KBr)cm.sup.-1 :                                     ______________________________________                                         ##STR506##            1770, 1680, 1605                                        ##STR507##            1770, 1710, 1680, 1610                                  ##STR508##            1770, 1660, 1600                                       ______________________________________                                         Note:                                                                         *A reaction was effected in hydrous tetrahydrofuran using (a)                 (4ethyl-2,3-dioxo-1-piperazine)-carbonyl chloride in place of                 5hydroxy-4-oxo-1,4-dihydro-2-pyridinecarboxylic acid and (b) sodium           hydrogencarbonate by ShottenBaumann method.                              

EXAMPLE 26

In 20 ml of water was dissolved 100 mg of disodium salt of(3R,5R,6R)-6-[DL-α-(p-acetoxyphenyl)sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.The solution was adjusted to pH 6.8 with a saturated aqueous sodiumhydrogencarbonate solution. Thereto was added, with ice cooling, 20 mgof an esterase (manufactured by Boehringer Mannheim) which had beendesalted using a continuous counter current dialyzer (Zeineh Dialyzermanufactured by Funakoshi Co.). The mixture was stirred at 35° C. for 4hours while maintaining the reaction mixture at pH 6.5 to 6.8 with asaturated aqueous sodium hydrogencarbonate solution. The reactionmixture was subjected to ultrafiltration using a hollow fiber membrane(membrane type: HI, manufactured by ASAHI CHEMICAL INDUSTRY, CO., LTD.).The filtrate was adjusted to pH 5.0 with 0.1N hydrochloric acid. Thesolvent was removed by distillation under reduced pressure. The residuewas purified by reversed phase column chromatography (eluant: water) andfreeze-dried to obtain 62.5 mg (yield: 67.0%) of disodium salt of(3R,5R,6R)-3-carboxy-6-[DL-α-(p-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1760, 1705, 1665, 1600

The compounds shown in Table 23 were obtained in the same manner.

In Table 23, R^(1a) shows a substituent of the following formula.

                  TABLE 23                                                        ______________________________________                                         ##STR509##                                                                   R.sup.1a                 IR(KBr)cm.sup.-1 :                                   ______________________________________                                         ##STR510##      (L) (D) 1770, 1720, 1660, 1600 1770, 1670, 1610               ##STR511##      (D)     1770, 1700, 1670, 1620                                ##STR512##      (L) (D) 1770, 1700, 1670, 1620 1765, 1700, 1670, 1620         ##STR513##      (L) (D)  1770, 1700, 1660, 1620 1765, 1700, 1670, 1620        ##STR514##      (D)     1770, 1720, 1670, 1610                                ##STR515##      (L) (D) (DL)                                                                          1770, 1720, 1670, 1615 1765, 1700-1660, 1620                                  1765, 1720, 1700, 1670, 1620                          ##STR516##      (D)     1765, 1700, 1665, 1610                               ______________________________________                                    

EXAMPLE 27

In the same manner as in Example 26, there was obtained disodium salt of(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-semicarbazonoethylideneaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1765, 1720, 1700, 1670, 1620

EXAMPLE 28

In 664 ml of methylene chloride was dissolved 83.0 g of(3R,5R,6R)-3-(3-benzylideneamino-2-oxo-imidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -60° C. To the solution were added 55.8 ml ofN,N-dimethylaniline and 39.3 g of phosphorus pentachloride in thisorder. The temperature of the mixture was elevated to -20° C. in 30minutes and then recooled to -60° C. To the reaction mixture was added66.3 ml of anhydrous methanol, and the mixture was heated to 0° C. in 30minutes and stirred at the same temperature for 30 minutes. 664 ml ofethyl acetate was added to the reaction mixture. The mixture was stirredfor 15 minutes with ice cooling. The resulting crystals were collectedby filtration, washed twice each with 83 ml of methylene chloride andonce with 83 ml of ethyl acetate, and dried under reduced pressure toobtain 57.5 g (yield: 79.0%) of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane hydrochloride.

IR (KBr) cm⁻¹ : 1790, 1720, 1705

The compounds shown in Table 24 were obtained in the same manner.

In Table 24, R and R¹⁴ each show a substituent of the following formula.

                  TABLE 24                                                        ______________________________________                                         ##STR517##                                                                   R                  R.sup.14  IR(KBr) cm.sup.-1 :                              ______________________________________                                         ##STR518##        DPM       1790, 1725, 1710                                  ##STR519##        "         1790, 1725, 1710                                  ##STR520##        PNB       1790, 1710                                       ______________________________________                                    

EXAMPLE 29

(1) 60.0 g of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanehydrochloride was suspended in a mixed solvent consisting of 450 ml ofmethylene chloride, 63 ml of anisole and 80 ml of nitromethane. Thesuspension was cooled to -30° C.

(2) 31.8 g of anhydrous aluminum chloride was dissolved in 70 ml ofnitromethane. The solution was dropwise added to the suspension preparedin (1) above, at -30° C. The mixture was stirred at -20° C. for 10minutes. The reaction mixture was poured into 1.2 liters of 1.5Nhydrochloric acid. The mixture was stirred for 30 minutes at roomtemperature and adjusted to pH 1.5 with a 20% aqueous sodium carbonatesolution. The resulting precipitate was collected by filtration andsuspended in 2.4 liters of water. The suspension was adjusted to pH 9.0with concentrated ammonia water. The insolubles were removed byfiltration with Celite. The filtrate was washed with 500 ml of ethylacetate, adjusted to pH 3.5 with 6N hydrochloric acid, and stirred for15 minutes with ice cooling. The resulting crystals were collected byfiltration and dried to obtain 36.0 g (yield: 92.0%) of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1705, 1640

The compounds shown in Table 25 were obtained in the same manner.

In Table 25, R shows a substituent of the following formula.

                  TABLE 25                                                        ______________________________________                                         ##STR521##                                                                   R                     IR(KBr) cm.sup.-1 :                                     ______________________________________                                         ##STR522##           1780, 1710, 1640                                         ##STR523##           1780, 1710, 1640                                        ______________________________________                                    

EXAMPLE 30

In 150 ml of methanol was suspended 10.0 g of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 9.2 g of 2,4-dinitrophenylhydrazine hydrochloride at20°-25° C. The mixture was stirred at the same temperature for 3 hours.100 ml of water was added to the reaction mixture. The mixture wasadjusted to pH 8.0 with concentrated ammonia water. The resultingcrystals were removed by filtration. To the filtrate was slowly addedconcentrated hydrochloric acid to adjust the filtrate to pH 1.5. To thefiltrate was added 2.5 g of active carbon, and the mixture was stirredat room temperature for 5 minutes. The active carbon was removed byfiltration and washed with water. The filtrate and washings werecombined and to the resulting mixture was added 3.9 g of sodium cyanateat room temperature in 60 minutes while maintaining the reaction mixtureat pH 1.6 to 2.1 with concentrated hydrochloric acid. After theaddition, the mixture was stirred at room temperature for 60 minutes.The resulting crystals were collected by filtration and suspended in 50ml of water. To the suspension was added concentrated ammonia water toadjust the suspension to pH 9.0. Then, 0.4 g of active carbon was added,and the mixture was stirred at room temperature for 5 minutes. Theactive carbon was removed by filtration and washed with water.Concentrated hydrochloric acid was added to a mixture of the washingsand the previously obtained filtrate to adjust the pH to 4.5. Themixture was stirred at room temperature for 30 minutes. The resultingcrystals were collected by filtration, washed with water and acetone inthis order, and dried under reduced pressure to obtain 5.81 g (yield:66.0%) of(3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1660, 1620

(3R,5R,6R)-6-amino-3-carboxy-3-[3-(p-methylbenzylideneamino)-2-oxoimidazolidin-1-yl-]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneand(3R,5R,6R)-6-amino-3-(3-anisylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanewere treated in the same manner to obtain(3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.The physical property (IR) of this product were identical with thatobtained above.

EXAMPLE 31

In 80 ml of methylene chloride was dissolved 7.50 g of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazoldin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 5 g ofS-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine. Themixture was stirred at room temperature for 2 hours. The reactionmixture was mixed with 80 ml of water, and the resulting mixture wasadjusted to pH 7.0 with a saturated aqueous sodium hydrogencarbonatesolution. The organic layer was separated, washed with water and asaturated aqueous sodium chloride solution in this order, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/acetone=1/0 to 25/1) to obtain 8.36 g(yield: 85.2%) of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(p-methoxybenzyloxycarbonylamino)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1795, 1710

EXAMPLE 32

In a mixed solvent consisting of 10 ml of methylene chloride and 10 mlof methanol was dissolved 0.20 g of(3R,5R,6R)-3-(3-formylmethylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-6-[DL-α-(p-nitrobenzyloxycarbonyl]-α-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 26 mg of methoxyamine hydrochloride. The mixture wasstirred at room temperature for 1 hour. The reaction mixture was mixedwith 10 ml of water. The resulting mixture was adjusted to pH 7 with asaturated aqueous sodium hydrogencarbonate solution. The organic layerwas separated, washed with water and a saturated aqueous sodium chloridesolution in this order, and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure. The residuewas purified by column chromatography (eluant: chloroform/acetone=20/1to 10/1) to obtain 0.15 g (yield: 72.1%) of(3R,5R,6R)-3-(p-nitrobenzyloxycarbonyl)-6-[DL-α-(p-nitrobenzyloxycarbonyl)-α-phenylacetamido]-3-[3-(N-methoxyiminoethylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1790, 1710

The compounds shown in Table 26 were obtained in the same manner.

In Table 26, R^(1a) and R each show a substituent of the followingformula.

                                      TABLE 26                                    __________________________________________________________________________     ##STR524##                                                                   R.sup.1a        R                 IR(KBr)cm.sup.-1 :                          __________________________________________________________________________     ##STR525##     NCHCHNOCH.sub.2 CO.sub.2 DPM                                                                    1785, 1725, 1670                             ##STR526##     NCHCHNNHCONH.sub.2                                                                              1780, 1720, 1680                            "               NCHCHNNHCHO       1790, 1730,                                                                   1680                                                         ##STR527##       1780, 1720, 1680                            "                                                                                              ##STR528##       1790, 1740, 1680                            PMBO            NCHCHNNHCONH.sub. 2                                                                             1785, 1730,                                                                   1720, 1690                                  __________________________________________________________________________

EXAMPLE 33

In 7 ml of methylene chloride was dissolved 0.70 g of(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -30° C. and mixed with 0.085 ml ofchlorosulfonyl isocyanate. The mixture was stirred for 30 minutes withice cooling. Then, 0.2 ml of a 16% ammonia-methanol solution was addedto the reaction mixture with ice cooling, and the resulting mixture wasstirred at the same temperature for 30 minutes. 5 ml of water was addedto the reaction mixture. The resulting mixture was adjusted to pH 2 with1N hydrochloric acid. The organic layer was separated and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/methanol=30/1 to 10/1) to obtain 0.60g (yield: 77.7%) of (3R,5R,6R)-3-[3-(3-aminosulfamoylureido)-2-oxo-imidazolidin-1-yl]-3-diphenylmethyloxycarbonyl-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1790, 1710

EXAMPLE 34

In 5 ml of benzene was dissolved 0.23 g of (3R,5R,6R)3-diphenylmethyloxycarbonyl-6-(DL-α-diphenylmethyloxycarbonyl-.alpha.-phenylacetamido)-3-(3-formylmethylideneamino-2-oxoimidazolidin-1-yl)-7-oxo4-thia-1-azabicyclo[3.2.0]heptane. Thereto was added 0.12 9 oftriphenylphosphoranylideneacetonitrile. The mixture was stirred at roomtemperature for 2 days. The reaction mixture was mixed with 10 ml ofwater and 10 ml of ethyl acetate. The mixture was adjusted to pH 7 witha saturated aqueous sodium hydrogencarbonate solution. The organic layerwas separated and dried over anhydrous magnesium sulfate. The solventwas removed by distillation under reduced pressure. The residue waspurified by column chromatography (eluant: benzene/ethyl acetate=3/1 to2/1) to obtain 0.10 g (yield: 42.4%) of(3R,5R,6R)-3-[3-(3-cyano-2-propenylideneamino)-2-oxoimidazolidin-1-yl]-3-diphenylmethyloxycarbonyl-6-(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1790, 1710

The following compound was obtained in the same manner.

(3R,5R,6R)-3-diphenylmethyloxycarbonyl-6-[DL-α(diphenylmethyloxycarbonyl)-γ-p-methoxybenzyloxyphenylacetamido]-7-oxo-3-[2-oxo-3-(5-piperidinocarbonyl-2,4-pentadienylideneamino)imidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1785, 1720, 1605

EXAMPLE 35

In 5 ml of methylene chloride was dissolved 320 mg of(3R,5R,6R)-6-[D-α-(p-acetoxyphenyl)-α-(p-methoxybenzyloxycarbonylamino)acetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -20° C. Thereto was dropwise added 0.78 ml ofan anisole solution containing 160 mg of anhydrous aluminum chloride at-20° to -10° C. After the dropwise addition, the mixture was stirred at-10° to 0° C. for 30 minutes. The reaction mixture was added to a mixedsolvent consisting of 10 ml of water and 15 ml of ethyl acetate. Theresulting mixture was adjusted to pH 1.0 with 2N hydrochloric acid. Theaqueous layer was separated and mixed with 10 ml of ethyl acetate and 10ml of tetrahydrofuran. The mixture was adjusted to pH 7.5 with asaturated aqueous sodium hydrogencarbonate solution. The insolubles wereremoved by filtration. The organic layer was separated, washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure to obtain 140 mg (yield: 54 9%) of(3R,5R,6R)-6-[D-α-(p-acetoxyphenyl)-α-aminoacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

EXAMPLE 36

In 22 ml of methylene chloride was suspended 220 mg of(3R,5R,6R)-6-[D-α-(p-acetoxyphenyl)-α-aminoacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 110 mg of a sulfur trioxidepyridine complex at roomtemperature, and the mixture was stirred for 3 hours at the sametemperature. The solvent was removed by distillation under reducedpressure. The residue was mixed with 15 ml of ethyl acetate and 15 ml ofwater. The mixture was adjusted to pH 7.0 with a saturated aqueoussodium hydrogencarbonate solution. The aqueous layer was separated andpurified by reversed phase column chromatography (eluant:water/acetonitrile=1/0 to 10/1) to obtain 40 mg (yield: 15.7%) of sodiumsalt of(3R,5R,6R)-6-[D-α-(p-acetoxyphenyl)-αphenyl)-α-sulfoaminoacetamido]-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710, 1670, 1600

EXAMPLE 37

In 5 ml of methylene chloride was dissolved 170 mg of(3R,5R,6R)-3-(3-carboxymethylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.The solution was cooled to -20° to -10° C. Thereto were added 0.034 mlof triethylamine and 0.023 ml of ethyl chlorocarbonate in this order.The mixture was stirred at -20° to -10° C. for 30 minutes. To thereaction mixture was added 0.14 ml of a 7.4N amm methanol solution at atemperature of -20° C. or below. The mixture was stirred for 1 hour withice cooling. The reaction mixture was added to a mixed solventconsisting of 10 ml of methylene chloride and 10 ml of water. Theresulting mixture was adjusted to pH 2.0 with 2N hydrochloric acid. Theorganic layer was separated, washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure. The residuewas purified by column chromatography (eluant: chloroform/acetone=10/1to 2/1)carbamoylmethylideneamino-2-oxoimidazolidin-1-yl)-3-carbamoylmethyldieneamino-6-(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1780, 1720, 1670

The following compound was obtained in the same manner.

(3R,5R,6R)-3-[3-(3-carbamoyl-2-allylidene)amino-2-oxoimidazolidin-1-yl]-3-diphenylmethyloxycarbonyl-6-(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane

(KBr) cm⁻¹ : 1790, 1730, 1670

EXAMPLE 38

In 10 ml of methylene chloride was dissolved 280 mg of(3R,5R,6R)-3-(3-carbamoylmethylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto were added 0.095 ml of trifluoroacetic anhydride and 0.108 ml ofpyridine. The mixture was stirred at room temperature for 20 minutes. 5ml of water was added to the reaction mixture. The mixture was adjustedto pH 3.0 with 1N hydrochloric acid. The organic layer was separated,washed with a saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/acetone=10/1 to 5/1) to obtain 110 mg(yield: 40.1%) of(3R,5R,6R)-3-(3-cyanomethylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

EXAMPLE 39

(1) 6.0 g of DL-(4-acetoxy-2-chlorophenyl)acetic acid was suspended in90 ml of methylene chloride. Thereto were added, with ice cooling, 2.75ml of oxalyl chloride and 50 μl of N,N-dimethylformamide. The mixturewas stirred at room temperature for 1 hour. The solvent was removed bydistillation under reduced pressure. The residue was dissolved in 90 mlof methylene chloride. Thereto was added 5.30 g of a sulfurtrioxide-dioxane complex with ice cooling. The mixture was stirred atroom temperature overnight. The solvent was removed by distillationunder reduced pressure. The residue was dissolved in 50 ml of anhydrousacetonitrile.

(2) In 100 ml of water was suspended 5.70 g of(3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added a 20% aqueous sodium carbonate solution with icecooling to adjust the pH to 9.0 to obtain a uniform solution. To thesolution was added, in 40 minutes, the acetonitrile solution prepared in(1) above, with ice cooling while maintaining the reaction mixture at pH7.0 to 7.5 with a 20% aqueous sodium carbonate solution. The mixture wasstirred at the same temperature for 10 minutes. 50 ml of ethyl acetatewas added thereto. The aqueous layer was separated, adjusted to pH 5.5with 2N hydrochloric acid, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (eluant:water) and freeze-dried to obtain each of isomers (diastereomers at6-position) of disodium salt of (3R,5R,6R)-6-[α-(4-acetoxy-2-chlorophenyl)-α-sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

L form [Eluted first in reversed phase column chromatography. 2.18 g(Yield: 20.0%)]

IR (KBr) cm⁻¹ : 1765, 1700, 1690, 1670, 1620

D form [Eluted later in reversed phase column chromatography. 2.38 g(Yield: 21.8%)]

IR (KBr) cm⁻¹ : 1765, 1700, 1685, 1670, 1620

The compounds shown in Table 27 were obtained in the same manner.

In Table 27, R^(1a) shows a substituent of the following formula.

                  TABLE 27                                                        ______________________________________                                         ##STR529##                                                                   R.sup.1a                 IR(KBr)cm.sup.-1 :                                   ______________________________________                                         ##STR530##      (L) (D) 1770, 1705, 1670, 1620 1770, 1700, 1670, 1620         ##STR531##      (L) (D) 1760, 1700, 1670, 1620 1760, 1700, 1670, 1620         ##STR532##      (L) (D)    -- 1765, 1720, 1700, 1665, 1610                    ##STR533##      (L)  (D)                                                                              1770, 1720, 1705, 1665, 1620 1760, 1705, 1685,                                1605                                                  ##STR534##      (L) (D) 1765, 1720, 1700, 1670, 1610 --                       ##STR535##      (L) (D) 1760, 1700, 1670, 1620 1760, 1705, 1670, 1620         ##STR536##      (L) (D) 1765, 1705, 1670, 1620 1765, 1705, 1685, 1670                                 1620                                                  ##STR537##      (L) (D) 1765, 1700, 1670, 1620 1765, 1710, 1680, 1670,                                1620                                                  ##STR538##      (L) (D) 1770, 1710, 1690, 1670,  1620 1760, 1705, 1690,                               1670, 1620                                            ##STR539##      (L) (D) 1760, 1700, 1670, 1620 1760, 1705, 1670, 1620         ##STR540##      (L) (D) 1775, 1700, 1690, 1680, 1620 1775, 1700, 1690,                                1680, 1620                                            ##STR541##      (L) (D) 1760, 1700, 1665, 1610 1760, 1700, 1670, 1610         ##STR542##      (L) (D) 1770, 1705, 1690, 1670, 1620 1770, 1705, 1690,                                1670, 1610                                            ##STR543##      (L) (D) 1765, 1705, 1670, 1620 1770, 1710, 1680, 1620         ##STR544##      (L) (D) 1770, 1705, 1670, 1625 1770, 1705, 1670, 1620         ##STR545##      --      1770, 1720, 1710, 1670, 1610                         ______________________________________                                    

EXAMPLE 40

In a mixed solvent consisting of 15 ml of methylene chloride and 2.2 mlof anisole was suspended 1.5 g of(3R,5R,6R)-3-diphenylmethyloxycarbonyl-6-(p-methoxybenzyloxycarbonylamino)-7-oxo-3-[2-oxo-3-(2-semicarbazonoethylideneamino)imidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptane.The suspension was cooled to -30° C. Thereto was added 7 ml of anitromethane solution containing 1.4 g of anhydrous aluminum chloride.The mixture was stirred at -20° C. for 3 hours. 10 ml of water wasadded. The mixture was adjusted to pH 8.5 with a saturated aqueoussodium hydrogen carbonate solution. The precipitated insolubles wereremoved by filtration with Celite. The aqueous layer of the filtrate wasseparated. To the separated aqueous layer was added, in 20 minutes, 10ml of an acetonitrile solution containing 1.23 g ofDL-α-(4,5-diacetoxy-2-chlorophenyl)-α-sulfoacetyl chloride prepared inthe same manner as in Example 39 (1), with ice cooling while maintainingthe reaction mixture at pH 7 to 8 with a 20% aqueous sodium carbonatesolution. The reaction mixture was then adjusted to pH 6 with 1Nhydrochloric acid. Thereto was added 10 ml of ethyl acetate. The aqueouslayer was separated and concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (eluant:water/acetonitrile=20/1 to 10/1) to obtain each of diastereomers of(3R,5R,6R)-3-carboxy-6-[o-(4,5-diacetoxy-2-chlorophenyl)-α-sulfoacetamido]-7-oxo-3-[2-oxo-3-(2-semicarbazonoethylideneamido)imidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptane.

L form [Eluted first in reversed phase column chromatography. 0.15 g(yield: 9.2%)]

IR (KBr) cm⁻¹ : 1770, 1710, 1680, 1620

D form [Eluted later in reversed phase column chromatography. 0.20 g(yield: 12.3%)]

IR (KBr) cm⁻¹ : 1765, 1710, 1680, 1620

EXAMPLE 41

In 10 ml of water was dissolved 460 mg of disodium salt of(3R,5R,6R)-3-carboxy-6-[D-α-(4-nitrophenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 200 mg of 5% palladiumcarbon. The mixture was stirredat room temperature for 3 hours in a hydrogen atmosphere. After thecompletion of the reaction, the insolubles were removed by filtrationand the filtrate was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (eluant: water) andfreeze-dried to obtain 300 mg (yield: 68.5%) of disodium salt of(3R,5R,6R)-6-[D-α-(4-aminophenyl)-α-sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1770, 1700, 1660, 1615

The following compound was obtained in the same manner.

Disodium salt of(3R,5R,6R)-6-[D-α-(4-amino-2-chlorophenyl)-α-sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1765, 1705, 1660, 1620

EXAMPLE 42

In 5 ml of water was dissolved 150 mg of disodium salt of(3R,5R,6R)-6-[D-α-(4-aminophenyl)-αsulfoacetamido[-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 120 mg of sodium cyanate in small portions with icecooling while maintaining the reaction mixture at pH 4 to 5 with 1Nhydrochloric acid. The mixture was stirred at room temperature for 10minutes. The reaction mixture was concentrated under reduced pressure.The residue was purified by reversed phase column chromatography(eluant: water) and freeze-dried to obtain 120 mg (yield: 74.5%) ofdisodium salt of(3R,5R,6R)-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-6-[D-.alpha.-sulfo-α-(4-ureidophenyl)acetamido]-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1700, 1660, 1605

The following compound was obtained in the same manner.

Disodium salt of(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4-ureidophenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1760, 1700, 1660, 1610

EXAMPLE 43

In 20 ml of methanol was dissolved 200 mg of disodium salt of(3R,5R,6R)-6-[D-α-(4-acetoxy-3-nitrophenyl)-α-sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.Thereto were added 0.14 ml of acetic anhydride and 150 mg of 5%palladium-carbon in this order. The mixture was stirred at roomtemperature for 3 hours in a hydrogen atmosphere. After the completionof the reaction, the insolubles were removed by filtration. The filtratewas mixed with 50 ml of water. The mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (eluant: water) to obtain 160 mg (yield: 78.4%) ofdisodium salt of(3R,5R,6R)-6-[D-α-(3-acetamido-4-hydroxyphenyl)-α-sulfoacetamido]-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1660, 1615

EXAMPLE 44

(1) 3.27 g of di-tri-n-butyl amine salt ofD-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetic acid was suspended in16.4 ml of methylene chloride. Thereto were added 1.30 ml oftrimethylchlorosilane and 2.73 ml of tri-n-butylamine with ice cooling.The mixture was stirred for 30 minutes at the same temperature. Theretowas added 0.60 ml of isopropyl chlorocarbonate at -15° to -10° C. Themixture was stirred at the same temperature for 1 hour to obtain asolution of mixed anhydride.

(2) In 16.4 ml of methanol was suspended 1.75 g of(3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.To the suspension was added 1.70 ml of tri-n-butylamine was added toobtain a solution. To the resulting solution was dropwise added themixed anhydride solution prepared in (1) above, at a temperature of -50°C. or below. The temperature of reaction mixture was elevated to roomtemperature in 1 hour and stirred for 1 hour at the same temperature. Tothe reaction mixture were added 2.86 ml of acetic acid and 4.5 ml of amethanol solution containing 1.50 g of sodium acetate trihydrate in thisorder. The resulting mixture was stirred at room temperature for 1 hour.The resulting precipitates were collected by filtration, dissolved in 10ml of water, and purified by reversed phase column chromatography(eluant: water) to obtain 2.08 g (yield: 65.2%) of disodium salt of(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1760, 1700, 1670, 1610

The following compounds were obtained in the same manner.

Disodium salt of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[DL-.alpha.-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1760, 1720, 1700, 1660, 1615

Disodium salt of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[DL-.alpha.-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1760, 1720, 1700, 1660, 1615

Disodium salt of(3R,5R,6)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[D-.alpha.-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane

Sodium salt of(3R,5R,6R)-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-3-diphenylmethyloxycarbonyl-7-oxo-3-(2oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane

Sodium salt of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane

EXAMPLE 45

In a mixed solvent consisting of 55 ml of acetonitrile and 18.5 ml ofwater was dissolved 3.70 g of disodium salt of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[D-.alpha.-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 2.54 g of 2,4-dinitrophenylhydrazine hydrochloride.The mixture was stirred at room temperature for 3 hours. To the reactionmixture was added 37 ml of water. The insolubles were removed byfiltration and washed with 8 ml of water. The filtrate and the washingswere combined and mixed with 50 ml of ethyl acetate. The mixture wasadjusted to pH 6.0 with a saturated aqueous sodium hydrogencarbonatesolution. The aqueous layer was separated, washed with 50 ml of ethylacetate, and adjusted to pH 4.0 with 1N hydrochloric acid. Thereto wasadded 370 mg of active carbon, and the mixture was stirred for 5 minutesat room temperature. The active carbon was removed by filtration andwashed with water. The filtrate and the washings were combined andconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (eluant: water). The eluate wasconcentrated to about 10 ml. The residue was dropwise added to 100 ml ofethanol. The mixture was stirred for 30 minutes. The resulting crystalswere collected by filtration, washed with 10 ml of ethanol, and driedunder reduced pressure to obtain 2.04 g (yield: 63.3%) of disodium saltof(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1765, 1700, 1665, 1615

The following compound was obtained in the same manner.

Disodium salt of(3R,5R,6R)-3-(3-amino-2-oxo-imidazolidin-1-yl)-3-carboxy-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1765, 1720, 1700-1660, 1615

EXAMPLE 46

(3R,5R,6R)-3-diphenylmethyloxycarbonyl-6-{DL-α-(p-methoxybenzyloxycarbonyl)-α-[4-(p-methoxybenzyloxy)phenyl]acetamido}-3-[3-p-nitrobenzyloxycarbonylaminomethylcarbonylamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanewas reacted in the same manner as in Example 16 and then in the samemanner as in Example 12 to obtain disodium salt of(3R,5R,6R)-3-(3-aminomethylcarbonylamino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[DL-α-carboxy-α-(p-hydroxyphenyl)acetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1720-1660, 1600

EXAMPLE 47

In a mixed solvent consisting of 1 ml of water and 1 ml of acetonitrilewas dissolved 100 mg of disodium salt of(3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-carboxy-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicylo[3.2.0]heptane.Thereto were added 0.022 ml of acrolein and a catalytic amount ofp-toluenesulfonic acid in this order. The mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (eluant: water/acetonitrile=1/0 to 97/3) and freeze-driedto obtain 64 mg (yield: 60.0%) of disodium salt of(3R,5R,6R)-3-carboxy-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-allylideneaminoimidazolidin-1-yl)-4-thia-1-azabicylo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1720, 1700-1660, 1620, 1600

By using cis-β-formylacrylic acid in place of acrolein, there wasobtained trisodium salt of(3R,5R,6R)-3-[3-(3-carboxy-2-allylideneamino)-2-oxoimidazolidin-1-yl]-3-carboxy-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1720, 1710, 1630, 1620

EXAMPLE 48

In 3 ml of N,N-dimethylformamide was dissolved 0.64 g of disodium saltof(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 0.12 ml of benzyl bromide. The mixutre was stirred atroom temperature for 2 days. The reaction mixture was subjected toevaporation to dryness under reduced pressure. The residue was dissolvedin a mixed solvent consisting of 5 ml of water and 10 ml of ethylacetate. The resulting mixture was adjusted to pH 6 with a saturatedaqueous sodium hydrogencarbonate solution. The aqueous layer wasseparated and purified by reversed phase column chromatography (eluant:water/acetonitrile=93/7 to 90/10) to obtain 0.32 g (yield: 45.2%) ofsodium salt of(3R,5R,6R)-3-benzyloxycarbonyl-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1775, 1720, 1700, 1670

The following compound was obtained in the same manner.

Sodium salt of(3R,5R,6R)-6-[D-α-(2-chloro-4,5-dihydrophenyl)-α-sulfoacetamido]-3-methoxycarbonyl-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane

IR (KBr) cm⁻¹ : 1770, 1710, 1670, 1650

EXAMPLE 49

30 ml of benzene was added to 1.00 g of(3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxo-imidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneand 0.46 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde. The mixture wassubjected to azeotropy and dehydration under reflux for 1 hour using aDean-Stark aparatus. The reaction mixture was cooled, and the solventwas removed by distillation under reduced pressure to obtain 1.40 g(yield: 98.6%) of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

EXAMPLE 50

In a mixed solvent consisting of 3.2 ml of 1,2-dichloroethane and 9.6 mlof anhyrous benzene was dissolved 640 mg of(3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto were added 640 mg of anhydrous magnesium sulfate and 980 mg ofnickel peroxide in this order with ice-cooling. The mixture was stirredat room temperature for 2.5 hours. The insolubles were removed byfiltration. The solvent was removed by distillation under reducedpressure. The residue was dissolved in a mixed solvent consisting of 5ml of methanol and 5 ml of methylene chloride. The mixture was stirredat room temperature for 1 hour. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform) to obtain 580 mg (yield: 87.1%) of(3R,5R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1720

EXAMPLE 51

In a mixed solvent consisting of 15 ml of methanol, 6 ml oftetrahydrofuran, 1.5 ml of water and 6 ml of methylene chloride wasdissolved 740 mg of(3R,5R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.Thereto was added 240 mg of a Girard reagent(2-hydrazino-N,N,N-trimethyl-2-oxoethanaminium chloride). The mixturewas stirred at room temperature for 1 hour. To the reaction mixture wereadded 30 ml of methylene chloride and 10 ml of water. The resultingmixture was adjusted to pH 7.0 with a saturated aqueous sodiumhydrogencarbonate solution. The organic layer was separated, washed witha saturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue was purified by column chromatography (eluant:benzene/ethyl acetate=5/1 to 1/1) to obtain 320 mg (yield: 60.6%) of(3R,5R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.

IR (KBr) cm⁻¹ : 1770, 1710

PREPARATION EXAMPLE 1

An aqueous disodium salt solution of(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptanewas treated in a conventional manner to obtain a freeze-dried andsterilized disodium salt. One gram (potency) of disodium salt wasdissolved in 20 ml of physiological saline solution to obtain aninjection.

PREPARATION EXAMPLE 2

An aqueous disodium salt solution of(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicylo[3.2.0]heptanewas treated in a conventional manner to obtain a freeze-dried andsterilized disodium salt. One gram (potency) of disodium salt wasdissolved in 20 ml of physiological saline to obtain an injection.

What is claimed is:
 1. A penam derivative represented by the followingformula or a pharmaceutically acceptable salt thereof: ##STR546##wherein R¹ represents a hydrogen atom, a formyl,2,6-dimethyloxyphenylphenyl-carbonyl or5-methyl-3-phenylisoxzazol-4-ylcarbonyl group or an acyl grouprepresented by the formula: ##STR547## wherein R⁹ represents anunsubstituted or substituted lower alkyl, lower alkenyl, aryl orheterocyclic group; Z represents an oxygen or sulfur atom or a linkage;Y¹ represents a hydrogen atom; Y² represents a hydrogen atom, halogenatom, a hydroxyl group, a carboxyl group, a sulfo group, a sulfoaminogroup, a amino group or a group of the formula, R¹⁰ CONH-- in which R¹⁰is an unsubstituted or substituted aryl, arylcarbonylamino,heterocyclicamino or heterocyclic group; and Y¹ and Y² may form, whentaken together, an unsubstituted or substituted lower alkoxyimino,cycloalkyloxyimino, aralkyloxyimino, lower alkylidene, loweralkenylidene, lower alkoxymethylene, halomethylene orheterocyclic-oxyimino group; R² represents a hydrogen atom or a loweralkyl group; R³ represents a hydrogen atom, a lower alkoxy group, alower alkylthio group or a formamido group; R⁴ represents a protected orunprotected carboxyl group or a carboxylato group; R represents a groupof the formula, --NHR⁵ or NR⁵ R⁶ (in which R⁵ and R⁶, may be the same ordifferent, represent hydroxyl groups, cyano groups, sulfo groups orunsubstituted or substituted lower alkyl, aryl, acyl, carbamoyl,sulfamoyl, lower alkylsulfonyl or heterocyclic groups), or a group ofthe formula, --N═CR⁵ R⁶ (in which R⁷ and R⁸, which may be the same ordifferent, represent hydrogen atoms or carboxyl groups, cyano groups orsubstituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl,aryl, amino, acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, loweralkylthio, ureido or heterocyclic groups, or R⁷ and R⁸ may form acycloalkene or heterocyclic ring with the carbon atom to which R⁷ and R⁸are attached); and n represents 1 or 2; each of the substituted loweralkyl, lower alkenyl, aryl, and heterocyclic groups in the definition ofR⁹ having at least one substituent selected from the group consisting ofhalogen atoms, hydroxyl group, amino group, amino-lower alkyl groups,carboxyl group, lower alkoxy groups, ureido group, acylamino groups,cyano group, sulfo group, carbamoyloxy group, sulfamoyl group, nitrogroup, oxo group and heterocyclic groups; each of the substituted aryl,arylcarbonylamino, heterocyclicamino and heterocyclic groups in thedefinition of R¹⁰ having at least one substituent selected from thegroup consisting of halogen atoms, hydroxyl group, oxo group, loweralkyl groups, halo-lower alkyl groups, hydroxyl-lower alkyl groups,lower alkylthio groups, lower alkylthio-lower alkyl groups, aryl groups,haloaryl groups, cycloalkyl groups, arylamino groups, loweralkylsulfonyl groups and sulfamoylarylamino groups; each of thesubstituted lower alkoxyimino, cycloalkyloxyimino, aralkyloxyimino,lower alkylidene, lower alkenylidene, lower alkoxymethylene,halomethylene and heterocyclic-oxyimino group in the definition of thegroup which Y¹ and Y² may form having at least one substituent selectedfrom the group consisting of halogen atoms, acyloxy groups and carboxylgroups, each of the substituted lower alkyl, lower alkenyl, loweralkynyl, aryl, amino, acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl,lower alkylsulfonyl or heterocyclic groups in the definition of R⁵ andR⁶ having at least one substituent selected from the group consisting ofhalogen atoms, halo-lower alkyl groups, lower alkyl groups, lower alkoxygroups, carboxyl-lower alkoxy groups, lower alkylthio groups,carboxyl-lower alkylthio groups, lower alkanoyloxy groups, loweralkoxycarbonyl groups, diphenylmethoxycarbonyl group, aryloxycarbonylgroups, hydroxyl-lower alkoxy groups, lower alkoxyimino groups, iminogroup, amino-lower alkyl groups, carboxyl-lower alkyl groups, loweralkoxycarbonyl-lower alkyl groups, lower alkoxycarbonylamino groups,nitrobenzyloxycarbonylamino group, cyano-lower alkylamino-lower alkylgroups, N,N-di-lower alkylamino groups, lower alkylsulfonyl groups,sulfamoyl-lower alkyl groups, aryl groups, aralkyl groups, carbamoylgroup, sulfo group acyl groups, oxo group, carbonyl group, nitro group,cyano group, amino group, hydroxyl group, ureido group, aralkyloxygroups, sulfamoyl group, thioxo group, methylenedioxy group,heterocyclic groups and heterocyclicthio groups; each of the substitutedlower alkyl, aryl, acyl, carbamoyl, sulfamoyl, lower alkylthio, ureidoand heterocyclic groups in the definition of R⁷ and R⁸ and each of thecycloalkene and heterocyclic ring in the definition of the group whichR⁷ and R⁸ may form having at least one substituent selected from thegroup consisting of halogen atoms, halo-lower alkyl groups, lower alkylgroups, lower alkoxy groups, carboxyl-lower alkoxy groups, loweralkylthio groups, carboxyl-lower alkylthio groups, lower alkanoyloxygroups, lower alkoxycarbonyl groups, diphenylmethoxycarbonyl group,aryloxycarbonyl groups, hydroxyl-lower alkyl groups, lower alkoxyiminogroups, imino group, amino-lower alkyl groups, carboxyl-lower alkylgroups, lower alkoxycarbonyl-lower alkyl groups, loweralkoxycarbonylamino groups, nitrobenzyloxycarbonylamino groups,cyano-lower alkylamino-lower alkyl groups, N,N-di-lower alkylaminogroups, lower alkylsulfonyl groups, sulfamoyl-lower alkyl groups, arylgroups, aralkyl groups, carbamoyl group, sulfo group, acyl groups, oxogroup, carboxyl group, nitro group, cyano group, amino group, hydroxylgroup, ureido group, aralkyloxy groups, sulfamoyl group, thioxo group,methylenedioxy group, heterocyclic groups and heterocyclicthio groups;wherein the substituent for each of R⁵, R⁶, R⁷ and R⁸ may have at leastone substituent selected from the group consisting of lower alkylgroups, amino group, oxo group, hydroxyl group, carbamoyl group,hydroxyl-lower alkyl groups, protected or unprotected carboxyl-loweralkyl groups, N,N-di-lower alkylamino groups, acylamino groups,heterocyclic groups, ureido group, trimethylammonioacetyl group, andguanidino group; wherein the term "acyl" in "acyl group", "acyloxygroup" and "acylamino group" means formyl, C₂₋₅ alkanoyl, C₃₋₅ alkenoyl,benzoyl, naphthoyl, thenoyl, furoyl, isonicotinoyl, nicotinoyl,1,4-dihydropyridin-2-ylcarbonyl or4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl; the term "aryl" in "arylgroup", "N,N'-di-lower alkylaminoaryl group", "arylamino group","arylcarbonylamino group", "sulfamoylarylamino group", "aryloxycarbonylgroup" and "haloaryl group" means phenyl, naphthyl or indanyl; the term"aralkyl" in "aralkyl group", "aralkyloxy group" and "aralkyloxyiminogroup" means benzyl, phenethyl, 4-methylbenzyl and naphthylmethyl; theterm "heterocyclic" in "heterocyclic group", "heterocyclic amino group","heterocyclic-oxyimino group" or "heterocyclicthio group" meansazetidinyl, thienyl, furyl, pyrrolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,oxazolyl, thiazolyl, tetrazolyl, 1,3-dithiolanyl, pyridinyl,1-hydroxyl-4-oxo-1,4-dihydropyridyl, 1,4-dihydropyridiyl, thiazolidinyl,thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrazolinyl, pyrrolidinyl,2-oxazolinyl, imidazolinyl, furazanyl, isothiazolyl,4,5-dihydrothiazolyl, 2,3-dihydrofuryl, 2,5-dihydrofuryl,tetrahydrofuryl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl,3-pyrrolinyl, 4,5-dihydropyrazolyl, isoxazolyl, isoxazolidinyl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, piperidinyl,piperazinyl, tetrahydropyrazinyl, morpholinyl, pyrimidinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 2H-3,4-dihydropyranyl,2H-5,6-dihydropyranyl, 1,4-oxazinyl, pyridazinyl, 2H-thiazinyl,perhydrooxazinyl, dihydrooxazinyl, chromenyl, benzothienyl,benzoisothiazolidinyl, imidazo[1,2-b][1,2,4]triazinyl,thieno[3,2-b]thienyl, benzotriazolyl, 1,2,3-benzothiadiazolyl,tetrazolo[5,1-b]pyridazinyl, 2,1,3-benzoxadiazolyl,imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-b][1,3]thiazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl,imidazo[1,2-a]pyrazinyl, 1,4-benzomorpholinyl, benzothiazolyl,isoinodlinyl, benzofuranyl, 1,4-benzothiomorpholinyl,1,3-benzoxazolidinyl, triazolo[1,5-a]pyrimidinyl, indolinyl, indazolyl,benzoxazolyl, henzoisoxazyolyl, purinyl, isoquinolyl, quinolyl,1,8-naphthyridinyl, 1,5-naphthyridinyl,1,1-dioxo-1,2-benzoisothiazolidinyl, 1,2-dihydro-4H-3,1-benzoxazinyl,1,2-benzoxazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl,quinuclidinyl, perhydroazaepinyl, or 3-pyrrolin-2-yl, and saidheterocyclic group, when containing a nitrogen atom as the heteratom,may be quaternized; and the term "heterocyclic ring" means azetidine,1,3-dithiolane, 1,4-dihydropyridine, thiazolidine, oxazolidine,imidazolidine, pyrazoline, pyrrolidine, 2-oxazoline, imidazoline,4,5-dihydrothiazole, 2,3-dihydrofuran, 2,5-dihydrofuran,tetrahydrofuran, 3-pyrroline, 4,5-dihydropyrazole, isoxazolidine,piperidine, piperazine, tetrahydropyrazine, morpholine,tetrahydro-pyrimidine, 2H-3,4-dihydropyran, 2H-5,6-dihydropyran,2H-thiazine, dihydrooxazine, chromene, benzoisothiazolidine,5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 1,4-benzomorpholine,isoindoline, 1,4-benzothiomorpholine, 1,3-benzoxazolidine, indoline,1,1-dioxo-1,2-benzoisothiazolidine, 1,2-dihydro-4H-3,1-benzoxazine orquinuclidine.
 2. A penam derivative or a pharmaceutically acceptablesalt thereof according to claim 1, wherein R² and R³ are hydrogen atoms.3. A penam derivative or a pharmaceutically acceptable salt thereofaccording to claim 1 or 2, wherein R¹ is an acyl group.
 4. A penamderivative or a pharmaceutically acceptable salt thereof according toclaim 1 or 2, wherein R is a group of the formula, --NHR⁵ in which R⁵ isas defined in claim
 1. 5. A penam derivative or a pharmaceuticallyacceptable salt thereof according to claim 4, wherein R⁵ is a sulfogroup or an acyl, sulfamoyl, lower alkylsulfonyl or carbamoyl groupwhich may be substituted by at least one substituent selected from thegroup consisting of a halogen atom, a lower alkyl group, a carbamoylgroup, a protected or unprotected carboxyl group, a protected orunprotected amino group, a protected or unprotected hydroxyl group, anoxo group, a ureido group and a sulfamoyl group.
 6. A penam derivativeor a pharmaceutically acceptable salt thereof according to claim 1 or 2,wherein R is a group of the formula, --N═CR⁷ R⁸ in which R⁷ and R⁸ areas defined in claim
 1. 7. A penam derivative or a pharmaceuticallyacceptable salt thereof to claim 6, wherein R⁷ is a hydrogen atom.
 8. Apenam derivative or pharmaceutically acceptable salt thereof accordingto claim 7, wherein R⁸ is a carboxyl group, a cyano group or a loweralkyl, lower alkenyl, lower alkynyl, aryl, acyl, carbamoyl orheterocyclic group which may be substituted by at least one substituentselected from the group consisting of a halogen atom, a cyano group, anoxo group, a nitro group, a sulfo group, a carboxyl group, a hydroxylgroup, a lower alkyl group, a lower alkoxy group, a hydroxyl-lower alkylgroup, a amino group, a carboxyl-lower alkyl group, an aryl group, alower alkoxyimino group, a di-lower alkylamino group, an imino group, acarbamoyl group, an acyl group, a heterocyclic group and aheterocyclicthio group; said lower alkyl, lower alkoxy, hydroxyl-loweralkyl, carboxyl-lower alkyl group, lower alkoxyimino, imino, carbamoyl,acyl, heterocyclic and heterocyclicthio group for the substituent of R⁸may be substituted by at least one substituent selected from the groupconsisting of a lower alkyl group, a amino group, a carbamoyl group, anoxo group, a hydroxyl-lower alkyl group, a N,N-di-lower alkylaminogroup, a carboxyl-lower alkyl group, a heterocyclic group, atrimethylammonioacetyl group, a ureido group and a guanidino group.
 9. Apenam derivative or pharmaceutically acceptable salt thereof accordingto claim 6, wherein R⁷ and R⁸ form a heterocyclic ring with the carbonatom to which R⁷ and R⁸ are attached.
 10. A penam derivative or apharmaceutically acceptable salt thereof according to claim 1 or 2wherein n is
 1. 11. A penam derivative or a pharmaceutically acceptablesalt thereof according to claim 10, wherein R¹ represents a group of theformula: ##STR548## wherein R⁹ represents a lower alkyl, aryl orheterocyclic group which may be substituted by at least one substituentselected from the group consisting of a halogen atom, a protected orunprotected hydroxyl group, a protected or unprotected amino group, aprotected or unprotected amino-lower alkyl group, a protected orunprotected carboxyl group, a lower alkoxy group, a ureido group, acyano group, a carbamoyloxy group and a nitro group; Z represents anoxygen or sulfur atom or a linkage; Y¹ represents a hydrogen atom; Y²represents a hydrogen atom, a protected or unprotected hydroxyl group, aprotected or unprotected carboxyl group, a sulfo group, a sulfoaminogroup, a protected or unprotected amino group or a group of the formula,R¹⁰ CONH-- in which R¹⁰ represents a heterocyclic group which may besubstituted by at least one substituent selected from the groupconsisting of a halogen atom, a protected or unprotected hydroxyl group,an oxo group, a lower alkyl group, an aryl group, a cycloalkyl group ora lower alkylsulfonyl group; and Y¹ and Y² form, when taken together, alower alkoxyimino or aralkyloxyimino group which may be substituted byat least one substituent selected from the group consisting of a halogenatom and a protected or unprotected carboxyl group. 12.(3R,5R,6R)-3-Carboxy-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-allylideneaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 13.(3R,5R,6R)-3-Carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-semicarbazonoethylideneaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 14.(3R,5R,6R)-3-Carboxy-3-{3-[(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methylideneamino]-2-oxoimidazolidin-1-yl}-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamino)-α-(p-hydroxyphenyl)acetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 15.(3R,5R,6R)-3-Carboxy-3-[3-(3-carboxyallylideneamino)-2-oxoimidazolidin-1-yl]-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 16.(3R,5R,6R)-6-[2-(2-Aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-carboxy-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 17.(3R,5R,6R)-3-Carboxy-6-[D-α-(2-chloro-4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 18.(3R,5R,6R)-3-Carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 19.(3R,5R,6R)-3-Carboxylato-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido]-3-{3-[2-(3-methyl-1-imidazolidinium)ethylideneamino]-2-oxoimidazolidin-1-yl}-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 20.(3R,5R,6R)-3-Carboxy-6-[D-α-(5-hydroxyl-4-oxo-1,4-dihydropyridin-2-ylcarboxamido)-α-(p-hydroxyphenyl)acetamido]-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 21.(3R,5R,6R)-3-Carboxy-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-.alpha.-phenylacetamido]-7-oxo-3-[3-(3,4-dihydroxybenzylideneamino)-2-oxoimidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 22.(3R,5R,6R)-3-Carboxy-6-[D-α-(2-fluoro-4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 23.(3R,5R,6R)-3-Carboxy-6-[D-α-(3-fluoro-4-hydroxyphenyl)-α-sulfoacetamido[-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 24.(3R,5R,6R)-3-Carboxy-6-[D-α-(4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof. 25.(3R,5R,6R)-3-Carboxy-6-[D-α-(3,4-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 26. An antibacterialagent comprising a penam derivative represented by the following formulaor a pharmaceutically acceptable salt thereof: ##STR549## wherein R¹represents a hydrogen atom, a formyl, 2,6-dimethyloxyphenylcarbonyl or5-methyl-3-phenylisoxazol-4-ylcarbonyl group or an acyl grouprepresented by the formula: ##STR550## wherein R⁹ represents anunsubstituted or substituted lower alkyl, lower alkenyl, aryl orheterocyclic group; Z represents an oxygen or sulfur atom or a linkage;Y¹ represents a hydrogen atom; Y² represents a hydrogen atom, halogenatom, a hydroxyl group, a carboxyl group, a sulfo group, a sulfoaminogroup, a amino group or a group of the formula R¹⁰ CONH-- in which R¹⁰is an unsubstituted or substituted aryl, arylcarbonylamino,heterocyclicamino or heterocyclic group; and Y¹ and Y² may form, whentaken together, an unsubstituted or substituted lower alkoxyimino,cycloalkyloxyimino, aralkyloxyimino, lower alkylidene, loweralkenylidene, lower alkoxymethylene, halomethylene orheterocyclic-oxyimino group; R² represents a hydrogen atom or a loweralkyl group; R³ represents a hydrogen atom, a lower alkoxy group, alower alkylthio group or a formamido group; R⁴ represents a protected orunprotected carboxyl group or a carboxylato group; R represents a groupof the formula, --NHR⁵ or --NR⁵ R⁶ (in which R⁵ and R⁶, which may be thesame or different, represent hydroxyl groups, cyano groups, sulfo groupsor unsubstituted or substituted lower alkyl, aryl, acyl, carbamoyl,sulfamoyl, lower alkylsulfonyl or heterocyclic groups), or a group ofthe formula --N═CR⁷ R⁸ (in which R⁷ and R⁸, which may be the same ordifferent, represent hydrogen atoms or carboxyl groups, cyano groups orsubstituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl,aryl, amino, acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, loweralkylthio, ureido or heterocyclic groups, or R⁷ and R⁸ may form acycloalkene or heterocyclic ring with the carbon atom to which R⁷ and R⁸are attached); and n represents 1 or 2; each of the substituted loweralkyl, lower alkenyl, aryl, and heterocyclic groups in the definition ofR⁸ having at least one substituent selected from the group consisting ofhalogen atoms, hydroxyl group, amino group, amino-lower alkyl groups,carboxyl group, lower alkoxy groups, ureido group, acylamino groups,cyano group, sulfo group, carbamoyloxy group, sulfamoyl group, nitrogroup, oxo group and heterocyclic groups; each of the substituted aryl,arylcarbonylamino, heterocyclicamino and heterocyclic groups in thedefinition of R¹⁰ having at least one substituent selected from thegroup consisting of halogen atoms, hydroxyl group, oxo group, loweralkyl groups, halo-lower alkyl groups, hydroxyl-lower alkyl groups,lower alkylthio groups, lower alkylthio-lower alkyl groups, aryl groups,haloaryl groups, cycloalkyl groups, arylamino groups, loweralkylsulfonyl groups and sulfamoylarylamino groups; each of thesubstituted lower alkoxyimino, cycloalkyloxyimino, aralkyloxyimino,lower alkylidene, lower alkenylidene, lower alkoxymethylene,halomethylene and heterocyclic-oxyimino groups in the definition of thegroup which Y¹ and Y² may form having at least one substituent selectedfrom the group consisting of halogen atoms, acyloxy groups and carboxylgroups; each of the substituted lower alkyl, aryl, acyl, carbamoyl,sulfamoyl, lower alkylsulfonyl or heterocyclic groups in the definitionof R⁵ and R⁶ having at least one substituent selected from the groupconsisting of halogen atoms, halo-lower alkyl groups, lower alkylgroups, lower alkoxy groups, carboxyl-lower alkoxy groups, loweralkylthio groups, carboxyl-lower alkylthio groups, lower alkanoyloxygroups, lower alkoxycarbonyl groups, diphenylmethoxycarbonyl group,aryloxycarbonyl groups, hydroxyl-lower alkyl groups, lower alkoxyiminogroups, imino group, amino-lower alkyl groups, carboxyl-lower alkylgroups, lower alkyloxycarbonyl-lower alkyl groups, loweralkoxycarbonylamino groups, nitrobenzyloxycarbonylamino group,cyano-lower alkylamino-lower alkyl groups, N,N-di-lower alkylaminogroups, lower alkylsulfonyl groups, sulfamoyl-lower alkyl groups, arylgroups, aralkyl groups, carbamoyl group, sulfo group, acyl groups, oxogroup, carboxyl group, nitro group, cyano group, amino group, hydroxylgroup, ureido group, aralkyloxy groups, sulfamoyl group, thioxo group,methylenedioxy group, heterocyclic groups and heterocyclicthio groups;each of the substituted lower alkyl, lower alkenyl, lower alkynyl, aryl,amino, acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, loweralkylthio, ureido and heterocyclic groups in the definition of R⁷ and R⁸and each of the cycloalkene and heterocyclic ring in the definition ofthe group which R⁷ and R⁸ may form having at least one substituentselected from the group consisting of halogen atoms, halo-lower alkylgroups, lower alkyl groups, lower alkoxy groups, carboxyl-lower alkoxygroups, lower alkylthio groups, carboxyl-lower alkylthio groups, loweralkanoyloxy groups, lower alkoxycarbonyl groups, diphenylmethoxycarbonylgroup, aryloxycarbonyl groups, hydroxyl-lower alkyl groups, loweralkoxyimino groups, imino group, amino-lower alkyl groups,carboxyl-lower alkyl groups, lower alkoxycarbonyl-lower alkyl groups,lower alkoxycarbonylamino groups, nitrobenzyloxycarbonylamino group,cyano-lower alkylamino-lower alkyl groups, N,N-di-lower alkylaminogroups, lower alkylsulfonyl groups, sulfamoyl-lower alkyl groups, arylgroups, aralkyl groups, carbamoyl group, sulfo group, acyl groups, oxogroup, carboxyl group, nitro group, cyano group, amino group, hydroxylgroup, ureido group, aralkyloxy groups, sulfamoyl group, thioxo group,methylenedioxy group, heterocyclic groups and heterocyclicthio groups;wherein the substituent for each of R⁵, R⁶, R⁷ and R⁸ may have at leastone substituent selected from the group consisting of lower alkylgroups, amino group, oxo group, hydroxyl group, carbamoyl group,hydroxyl-lower alkyl groups, carboxyl-lower alkyl groups, N,N-di-loweralkylamino groups, acylamino groups, heterocyclic groups, ureido group,trimethylammonioacetyl group, and guanidino group; wherein the term"acyl" in "acyl group", "acyloxy group" and "acylamino group" meansformyl, C₂₋₅ alkanoyl, C₃₋₅ alkenoyl, benzoyl, naphthoyl, thenoyl,furoyl, isonicotinoyl, nicotinoyl, 1,4-dihydropyridin-2-ylcarbonyl or4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl; the term "aryl" in "arylgroup", "arylcarbonylamino group", "sulfamoylarylamino group","aryloxycarbonyl group" and "haloaryl group" means phenyl, naphthyl orindanyl; the term "aralkyl" in "aralkyl group", "aralkyloxy group" and"aralkyloxyimino group" means benzyl, phenethyl, 4-methylbenzyl ornaphthylmethyl; the term "heterocyclic" in "heterocyclic group","heterocyclic amino group", "heterocyclic-oxyimino group", or"heterocyclicthio group" means azetidinyl, thienyl, furyl, pyrrolyl,1,2,4-tri-azolyl, 1,2,3-triazolyl, oxazolyl, thiazolyl, tetrazolyl,1,3-dithiolanyl, pyridyl, 1-hydroxyl-4-oxo-1,4-dihydropyridyl,1,4-dihydropyridyl, thiazolidinyl, oxazolidinyl, imidazolidinyl,pyrazolinyl, pyrrolidinyl, 2-oxazolinyl, imidazolinyl, furazanyl,isothiazolyl, 4,5-dihydrothiazolyl, 2,3-dihydrofuryl, 2,5-dihydrofuryl,tetrahydrofuryl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl,3-pyrrolinyl, 4,5-dihydropyrazolyl, isoxazolyl, isoxazolidinyl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, piperidinyl,piperazinyl, tetrahydropyrazinyl, morpholinyl, pyrimidinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyll, 2H-3,4-dihydropyranyl,2H-5,6-dihydropyranyl, 1,4-oxazinyl, pyridazinyl, 2H-thiazinyl,perhydrooxazinyl, dihydrooxazinyl, chromenyl, benzothienyl,benzoisothiazolidinyl, imidazo[1,2-b][1,2,4-triazinyl,thieno[3,2-b]thienyl, benzotriazolyl, 1,2,3-benzothiadiazolyl,tetrazolo[5,1-b]pyridazinyl, 2,1,3-benzoxadiaolyl,imidazo[1,2-b]pyridyl, imidazo[1,2-b]pyrimidinyl,imidazo[1,2-b][1,3]thiazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl,imidazo[1,2-b]pyrazinyl, 1,4-benzomorpholinyl, benzothiazolyl,isoindolinyl, benzofuranyl, 1,4-benzothiomorpholinyl,1,3-benzoxazolidinyl, triazolo[1,5-a]pyrimidinyl, indolinyl, indazolyl,benzoxazolyl, benzoisoxazolyl, purinyl, isoquinolyl, quinolyl,1,8-naphthyridinyl, 1,5-naphthyridinyl,1,1-dioxo-1,2-benzoisothiazolidinyl, 1,2-dihydro-4H-3,1-benzoxazinyl,1,2-benzoxazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl,quinuclidinyl, perhydroazaepinyl, or 3-pyrrolin-2-yl, and saidheterocyclic group, when containing a nitrogen atom as the heteroatom,may be quaternized; and the term "heterocyclic ring" mentioned for R⁷and R⁸ represents azetidine, 1,3-dithiolane, 1,4-dihydropyridine,thiazolidine, oxazolidine, imidazolidine, pyrazoline, pyrrolidine,2-oxazoline, imidazoline, 4,5-dihydrothiazole, 2,3-dihydrofuran,2,5-dihydrofuran, tetrahydrofuran, 3-pyrroline, 4,5-dihydropyrazole,isoxazolidine, piperidine, piperazine, tetrahydropyrazine, morpholine,tetrahydro-pyrimidine, 2H-3,4-dihydropyran, 2H-5,6-dihydropyran,2H-thiazine, dihydrooxazine, chromene, benzoisothiazolidine,5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 1,4-benzomorpholine,isoindoline, 1,4-benzothiomorpholine, 1,3-benzoxazolidine, indoline,1,1-dioxo-1,2-benzoisothiazolidine, 1,2-dihydro-4H-3,1-benzoxazine orquinuclidine, and a pharmaceutically acceptable carrier.
 27. Anantibacterial agent according to claim 26, wherein R² and R³ arehydrogen atoms.
 28. An antibacterial agent according to claim 26 or 27,wherein R¹ is a formyl, 2,6-dimethyloxyphenylcarbonyl or5-methyl-3-phenylisoxazol-4-ylcarbonyl group or a group represented bythe formula: ##STR551## wherein R⁹, Y¹, Y² and Z are as defined in claim26.
 29. An antibacterial agent according to claim 26 or 27, wherein R isa group of the formula, --NHR⁵ in which R⁵ is as defined in claim 26.30. An antibacterial agent according to claim 29, wherein R⁵ is a sulfogroup or an acyl, sulfamoyl, lower alkylsulfonyl or carbamoyl groupwhich may be substituted by at least one substituent selected from thegroup consisting of a halogen atom, a lower alkyl group, a carbamoylgroup, a protected or unprotected carboxyl group, a protected orunprotected amino group, a protected or unprotected hydroxyl group, anoxo group, a ureido group and a sulfamoyl group.
 31. An antibacterialagent according to claim 26 or 27, wherein R is a group of the formula,--N═CR⁷ R⁸ in which R⁷ and R⁸ are as defined in claim
 26. 32. Anantibacterial agent according to claim 31, wherein R⁷ is a hydrogenatom.
 33. An antibacterial agent according to claim 26 or 27, wherein nis
 1. 34. An antibacterial agent according to claim 32, wherein R⁸ is acarboxyl group, a cyano group or a lower alkyl, lower alkenyl, loweralkynyl, aryl, acyl, carbamoyl or heterocyclic group which may besubstituted by at least one substituent selected from the groupconsisting of a halogen atom, a cyano group, an oxo group, a nitrogroup, a sulfo group, a carboxyl group, a hydroxyl group, a lower alkylgroup, a lower alkoxy group, a hydroxyl-lower alkyl group, a aminogroup, a carboxyl-lower alkyl group, an aryl group, a lower alkoxyiminogroup, a di-lower alkylamino group, an imino group, a carbamoyl group,an acyl group, a heterocyclic group and a heterocyclicthio group; saidlower alkyl, lower alkoxy, hydroxyl-lower alkyl, carboxyl-lower alkyl,lower alkoxyimino, imino, carbamoyl, acyl, heterocyclic andheterocyclicthio group for the substituent of R⁸ may be substituted byat least one substituent selected from the group consisting of a loweralkyl group, a amino group, a carbamoyl group, an oxo group, ahydroxyl-lower alkyl group, an N,N-di-lower alkylamino group, acarboxy-lower alkyl group, a heterocyclic group, atrimethylammonioacetyl group, a ureido group and a guanidino group. 35.An antibacterial agent according to claim 31, wherein R⁷ and R⁸ form aheterocyclic ring with the carbon atom to which R⁷ and R⁸ are attached.36. An antibacterial agent according to claim 33, wherein R¹ representsa group of the formula: ##STR552## wherein R⁹ represents a lower alkyl,aryl or heterocyclic group which may be substituted by at least onesubstituent selected from the group consisting of a halogen atom, aprotected or unprotected hydroxyl group, a protected or unprotectedamino group, a protected or unprotected amino-lower alkyl group, aprotected or unprotected carboxyl group, a lower alkoxy group, a ureidogroup, a cyano group, a carbamoyloxy group and a nitro group; Zrepresents an oxygen or sulfur atom or a linkage; Y¹ represents ahydrogen atom; Y² represents a hydrogen atom, a protected or unprotectedhydroxyl group, a protected or unprotected carboxyl group, a sulfogroup, a sulfoamino group, a protected or unprotected amino group or agroup of the formula, R¹⁰ CONH-- in which R¹⁰ represents a heterocyclicgroup which may be substituted by at least one substituent selected fromthe group consisting of a halogen atom, a protected or unprotectedhydroxyl group, an oxo group, a lower alkyl group, an aryl group, acycloalkyl group or a lower alkylsulfonyl group; and Y¹ and Y² form,when taken together, a lower alkoxyimino or aralkyloxyimino group whichmay be substituted by at least one substituent selected from the groupconsisting of a halogen atom and a protected or unprotected carboxylgroup.
 37. An antibacterial agent according to claim 26, wherein thepenam derivative is(3R,5R,6R)-3-carboxy-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-allylideneaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 38. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-semicarbazonoethylideneaminoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 39. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-3-{3-[(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methylideneamino]-2-oxoimidazolidin-1-yl}-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(phydroxyphenyl)acetamido]-7-oxo-4-thia-1-azabicyclo-3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 40. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-3-[3-(3-carboxyallylideneamino)-2-oxoimidazolidin-1-yl]-6-[DL-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 41. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-6-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-carboxy-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo-3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 42. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo-3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 43. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(2-chloro-4,5-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 44. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxylato-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido]-3-{3-[2-(3-methyl-1-imidazolidinium)ethylideneamino]-2-oxoimidazolidin-1-yl}-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 45. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(5-hydroxyl-4-oxo-1,4-dihydropyridin-2-ylcaboxyamido)-α-(p-hydroxyphenyl)acetamido]-3-[3-(1,3-dithiolan-2-ylideneamino)-2-oxoimidazolidin-1-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 46. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-phenylacetamido]-7-oxo-3-[3-(3,4-dihydroxybenzylideneamino)-2-oxoimidazolidin-1-yl]-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 47. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(2-fluoro-4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 48. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(3-fluoro-4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 49. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(4-hydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 50. An antibacterialagent according to claim 26, wherein the penam derivative is(3R,5R,6R)-3-carboxy-6-[D-α-(3,4-dihydroxyphenyl)-α-sulfoacetamido]-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt thereof.
 51. A method of treatingbacterial infection comprising administering an antibacteriallyeffective amount of a penam derivative or a pharmaceutically acceptablesalt thereof as defined in claim 1 to a patient in need thereof.